@article {pmid41517810,
year = {2026},
author = {Lee, S and Chang, JW},
title = {From Ablation to Neuromodulation Platform: The Evolving Role of Magnetic Resonance-Guided Focused Ultrasound in Functional Neurosurgery.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {1},
pages = {17-41},
doi = {10.3988/jcn.2025.0563},
pmid = {41517810},
issn = {1738-6586},
support = {/HI/NHLBI NIH HHS/United States ; },
abstract = {Magnetic resonance-guided focused ultrasound (MRgFUS) has rapidly evolved from an experimental concept into a versatile platform in functional neurosurgery. Initially pioneered as a noninvasive thermal ablation modality for essential tremor, MRgFUS has since gained regulatory approval and demonstrated durable long-term efficacy. Its clinical applications have expanded to include Parkinson's disease, chronic pain, psychiatric disorders, and investigational use in dystonia, epilepsy, and brain tumors. Beyond lesioning, low-intensity focused ultrasound enables reversible neuromodulation and transient blood-brain barrier opening, facilitating drug and gene delivery in conditions such as Alzheimer's disease and glioblastoma. Comparative analyses highlight MRgFUS as an incisionless alternative to traditional modalities like deep brain stimulation, radiofrequency ablation, and radiosurgery, offering unique advantages in precision, safety, and patient acceptability while retaining certain limitations, including irreversibility and eligibility constraints due to skull properties. Emerging innovations-such as dual-target strategies, staged bilateral procedures, adaptive focusing technologies, and integration with immuno- or gene therapies-are expanding its therapeutic potential. Collectively, these advances position MRgFUS as not only an ablative tool but also a transformative neuromodulation platform with broad implications for the treatment of movement disorders, neuropsychiatric disease, and neurodegeneration.},
}

@article {pmid41517803,
year = {2025},
author = {Das, R and Chatterjee, A and Roy, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106410},
doi = {10.1002/alz70856_106410},
pmid = {41517803},
issn = {1552-5279},
mesh = {Humans ; Magnetic Resonance Imaging ; *Alzheimer Disease/pathology/diagnostic imaging ; Male ; Female ; *Hippocampus/pathology/diagnostic imaging ; Aged ; *Biomarkers ; Disease Progression ; Atrophy/pathology ; Aged, 80 and over ; Longitudinal Studies ; *Parahippocampal Gyrus/pathology/diagnostic imaging ; Neuropsychological Tests ; Bayes Theorem ; },
abstract = {BACKGROUND: Alzheimer's disease is characterized by progressive atrophy of hippocampus and parahippocampal structures including entorhinal cortex and parahippocampal gyrus. Predicting longitudinal volume changes remains challenging as they can occur due to normal ageing and disease progression.

METHOD: From the ADNI dataset (n = 480), we used two years of baseline data including demographics, cognitive assessment scores (CDR-SB, MMSE), and FreeSurfer-extracted MRI measurements to predict third and fourth-year Hippocampus volume, parahippocampal volume and thickness. We employed a GRU-based Bayesian Encoder-Decoder architecture (GRU-BEND) with a 70:10:20 train-validation-test split. We evaluated our model over five-fold cross-validation and used the Integrated Gradient method for feature importance analysis. Figure 1 shows the degradation of the region's volumes over the year for different diagnosis cohorts.

RESULT: The model demonstrated strong predictive performance for all the target variables. We employed the metrics Mean Absolute Error (MAE) and Mean Absolute Percentage Error (MAPE) to evaluate our model. As expected, the predictions for the third year were more accurate than the fourth year. MAPE for the third year ranged between 4.3% to 4.9%, while 5.1% to 6.6% for the fourth year. MAE ranged between 0.03 to 0.06. The Left and right hippocampus volume prediction was most accurate over both years (Y3: MAE: 0.039±0.002, MAPE: 4.4±0.1%; Y4: MAE: 0.045±0.003, MAPE: 5.1%). The important features contributing to the predictions for hippocampus (left) and parahippocampal volume (left) are shown below in Figure 2 and 3. The role of CDR-SB and MMSE in the prediction was minimal. Surprisingly, amygdala and ventricle volume were among the least contributing factors for hippocampus predictions.

CONCLUSION: In this study, we demonstrate that a GRU-BEND model which is able to effectively predict longitudinal changes in volumes of hippocampal and parahippocampal structures in Alzheimer's disease based on two years of data. This may be helpful in prognosticating patients and quantitative estimation of treatment effects.},
}

Humans
Magnetic Resonance Imaging
*Alzheimer Disease/pathology/diagnostic imaging
Male
Female
*Hippocampus/pathology/diagnostic imaging
Aged
*Biomarkers
Disease Progression
Atrophy/pathology
Aged, 80 and over
Longitudinal Studies
*Parahippocampal Gyrus/pathology/diagnostic imaging
Neuropsychological Tests
Bayes Theorem

@article {pmid41517524,
year = {2025},
author = {Abboud, I and Xu, E and Xu, S and Alhasany, A and Wang, Z and Wu, X and Astraea, N and Jiang, F and Hu, ZJ and Chan, JW},
title = {Emerging Oculomic Signatures: Linking Thickness of Entire Retinal Layers with Plasma Biomarkers in Preclinical Alzheimer's Disease.},
journal = {Journal of clinical medicine},
volume = {15},
number = {1},
pages = {},
doi = {10.3390/jcm15010275},
pmid = {41517524},
issn = {2077-0383},
support = {UL1 TR001872/NH/NIH HHS/United States ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is the leading cause of dementia, which is an inevitable consequence of aging. Early detection of AD, or detection during the pre-AD stage, is beneficial, as it enables timely intervention to reduce modifiable risk factors, which may help prevent or delay the progression to dementia. On the one hand, plasma biomarkers have demonstrated great promise in predicting cognitive decline. On the other hand, in recent years, ocular imaging features, particularly the thickness of retinal layers measured by spectral-domain optical coherence tomography (SD-OCT), are emerging as possible non-invasive, non-contact surrogate markers for early detection and monitoring of neurodegeneration. This pilot study aims to identify retinal layer thickness changes across the entire retina linked to plasma AD biomarkers in cognitively healthy (CH) elderly individuals at risk for AD. Methods: Eleven CH individuals (20 eyes total) were classified in the pre-AD stage by plasma β-amyloid (Aβ)42/40 ratio < 0.10 and underwent SD-OCT. A deep-learning-derived automated algorithm was used to segment retinal layers on OCT (with manual correction when needed). Multiple layer thicknesses throughout the entire retina (including the inner retina, the outer retina, and the choroid) were measured in the inner ring (1-3 mm) and outer ring (3-6 mm) of the Early Treatment Diabetic Retinopathy Study (ETDRS). Relationships between retinal layers and plasma biomarkers were analyzed by ridge regression/bootstrapping. Results: Results showed that photoreceptor inner segment (PR-IS) thinning had the largest size effect with neurofilament light chain. Additional findings revealed thinning or thickening of the other retinal layers in association with increasing levels of glial fibrillary acidic protein and phosphorylated tau at threonine 181 and 217 (p-tau181 and p-tau217). Conclusions: This pilot study suggests that retinal layer-specific signatures exist, with PR-IS thinning as the largest effect, indicating neurodegeneration in pre-AD. Further research is needed to confirm the findings of this pilot study using larger longitudinal pre-AD cohorts and comparative analyses with healthy aging adults.},
}

@article {pmid41516328,
year = {2026},
author = {Cipriano, GL and Floramo, A and Argento, V and Oddo, S and Artimagnella, O},
title = {Mutant Tau (P301L) Enhances Global Protein Translation in Differentiated SH-SY5Y Cells by Upregulating mTOR Signalling.},
journal = {International journal of molecular sciences},
volume = {27},
number = {1},
pages = {},
doi = {10.3390/ijms27010455},
pmid = {41516328},
issn = {1422-0067},
support = {RRC-2025-23686388//Ministero della Salute/ ; },
mesh = {Humans ; *TOR Serine-Threonine Kinases/metabolism/genetics ; *tau Proteins/genetics/metabolism ; *Protein Biosynthesis ; *Signal Transduction ; Up-Regulation ; Cell Line, Tumor ; *Mutation ; Neurons/metabolism ; Sirolimus/pharmacology ; Cell Differentiation ; },
abstract = {Altered protein synthesis plays a key role in ageing and multiple neurodegenerative diseases. In Alzheimer's disease and other tauopathies, the intracellular accumulation of hyperphosphorylated Tau disrupts several cellular processes, including mRNA translation. Although Tau interacts with ribosomal proteins and modulates translational selectivity, its effects on global protein synthesis remain poorly understood. Studies report reduced translation in later disease stages but increased translation early in pathology. To clarify Tau's impact in human neurons, we used SH-SY5Y cells overexpressing the P301L mutant form of Tau and quantified global protein synthesis using the SUnSET (Surface Sensing of Translation) puromycin-incorporation assay. We found that Tau-P301L expression greatly increased global translation by upregulating mTOR/S6 pathway. These effects were abolished by rapamycin treatment, indicating that Tau-driven translational upregulation is mTOR-dependent. Given that impaired translational control can disrupt synaptic plasticity and memory, Tau-induced alterations in protein synthesis may contribute to tauopathy progression and identify mTOR signalling as a potential therapeutic target.},
}

Humans
*TOR Serine-Threonine Kinases/metabolism/genetics
*tau Proteins/genetics/metabolism
*Protein Biosynthesis
*Signal Transduction
Up-Regulation
Cell Line, Tumor
*Mutation
Neurons/metabolism
Sirolimus/pharmacology
Cell Differentiation

@article {pmid41516246,
year = {2025},
author = {Kvetnoy, I and Kheyfets, O and Safaniev, L and Kheifets, V and Mironova, E and Kvetnaia, T and Mazzoccoli, G and Prashchayeu, K and Gavrilova, A},
title = {Signaling Molecules and Diagnosis of Cognitive Disorders: Current State and Prospects.},
journal = {International journal of molecular sciences},
volume = {27},
number = {1},
pages = {},
doi = {10.3390/ijms27010372},
pmid = {41516246},
issn = {1422-0067},
mesh = {Humans ; Biomarkers/metabolism ; *Signal Transduction ; *Alzheimer Disease/metabolism/diagnosis ; Dementia, Vascular/metabolism/diagnosis ; *Cognition Disorders/diagnosis/metabolism ; *Cognitive Dysfunction/diagnosis/metabolism ; },
abstract = {Cognitive disorders present significant medical and social challenges nowadays, due to their high prevalence, progressive course and a lack of effective methods for treatment of neurodegenerative diseases and comorbid pathologies. An important area of research is the identification of molecular biomarkers that reflect early pathophysiological changes and facilitate a more accurate biological characterization of cognitive impairment. This study provides an overview of the most relevant signaling molecules for diagnosing cognitive disorders. It presents data on the effectiveness of using comprehensive panels of molecular biomarkers in clinical practice, including β-amyloid, CD34, claudin, DRP1, endothelin-1, NF-kB, PINK1, RAGE, S100, α-synuclein, and tau protein, in patients with Alzheimer's disease (AD) and vascular dementia (VD). The study results demonstrate that cumulative changes in the expression of signaling molecules reflect various neurodegenerative and vascular-associated biological processes. The data obtained are comparative in nature and require further validation before potential clinical application.},
}

Humans
Biomarkers/metabolism
*Signal Transduction
*Alzheimer Disease/metabolism/diagnosis
Dementia, Vascular/metabolism/diagnosis
*Cognition Disorders/diagnosis/metabolism
*Cognitive Dysfunction/diagnosis/metabolism

@article {pmid41515488,
year = {2026},
author = {Huang, Y and Li, X and Dai, L and Cheng, M and Zhao, L and Shen, Y and Xie, J and Luo, X},
title = {Antioxidant, Anti-Inflammatory, and Chemical Composition Analysis of In Vitro Huperzia serrata Thallus and Wild Huperzia serrata.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {1},
pages = {},
doi = {10.3390/molecules31010195},
pmid = {41515488},
issn = {1420-3049},
support = {20232ACB2050009//Natural Science Foundation of Jiangxi Province, China/ ; 32060074//National Natural Science Foundation of China/ ; 20204BCJ22024//Major Academic and Technical Leader Training Project of Jiangxi Province/ ; },
mesh = {*Antioxidants/pharmacology/chemistry ; *Anti-Inflammatory Agents/pharmacology/chemistry ; *Huperzia/chemistry ; Animals ; *Plant Extracts/chemistry/pharmacology ; Mice ; Sesquiterpenes/pharmacology/chemistry ; Alkaloids/pharmacology/chemistry ; RAW 264.7 Cells ; },
abstract = {Huperzine A is a preferred treatment option for Alzheimer's disease. Huperzia serrata (Thunb. ex Murray) Trev. (H. serrata) has garnered significant attention for its ability to produce Huperzine A (HupA). However, natural populations of wild H. serrata (WH) are rapidly declining. Fortunately, our group obtained two types of H. serrata thalli (OT and ST) capable of stably producing Huperzine A, which have the potential to serve as an alternative resource to WH. To evaluate the feasibility of this strategy, we conducted a comprehensive assessment of both WH and H. serrata thallus. The results indicated that compared to WH, ST and OT exhibited stronger anti-inflammatory and antioxidant activities, with lower cytotoxicity. Notably, ST demonstrated a strong radical scavenging activity, reaching 93.23% (DPPH at 0.2 μg/mL) and 99.87% (ABTS at 4 μg/mL), and reduced nitrite production from 10.29 μM to 6.51 μM at 50 µg/mL. GC-MS and widely targeted metabolomics analyses revealed that the higher antioxidant and anti-inflammatory activities for ST and OT were due to higher concentrations of phenolic acids and flavonoids compared to WH. In addition, the HupA content in ST reached 36.56% of that found in WH. KEGG enrichment analysis revealed that the flavonoid, phenylalanine, and phenylpropanoid biosynthesis pathways may be involved in regulating the antioxidant activity. P-coumaroyl quinic acid and caffeoyl quinic acid are the crucial metabolites for antioxidant activity. These findings suggested that the H. serrata thallus could serve as a sustainable alternative to WH.},
}

*Antioxidants/pharmacology/chemistry
*Anti-Inflammatory Agents/pharmacology/chemistry
*Huperzia/chemistry
Animals
*Plant Extracts/chemistry/pharmacology
Mice
Sesquiterpenes/pharmacology/chemistry
Alkaloids/pharmacology/chemistry
RAW 264.7 Cells

@article {pmid41514478,
year = {2026},
author = {Noman, M and Qadir, H and Ahmed, S and Rehman, NU and Shah, FA and Riaz, M and Ahmad, N and Ul-Haq, Z and Irshad, N},
title = {Santonin Attenuates Alzheimer's-Like Pathology via Multitarget Modulation of the NLRP3 Inflammasome, BDNF Signaling, and Amyloidogenic Pathways: An Integrated Experimental and Computational Study.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00957},
pmid = {41514478},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant cause of dementia, characterized by amyloid β (Aβ) plaques and tau tangles that disrupt neurons in memory-related brain regions. This study explores the therapeutic potential of santonin using integrated in silico, in vitro, and in vivo approaches. Molecular docking identified santonin as a promising acetylcholinesterase, NOD-like receptor family, pyrin domain-containing 3 (NLRP3), brain-derived neurotrophic factor (BDNF), and nuclear factor kappa B (NF-κB) ligand with significant binding affinities and supportive interaction scores supported by molecular dynamics simulations with significant multitarget therapeutic relevance. In vitro assays demonstrated that santonin has measurable inhibition of cholinesterase enzymes, showing significant effects on butyrylcholinesterase and acetylcholinesterase enzymes. Behavioral analysis revealed that santonin produced dose-dependent improvements in memory and exploratory behaviors, indicating significant neuroprotective effects against streptozotocin (STZ)-induced impairments. Histological analysis showed that santonin preserved neuronal architecture, enhanced neuronal density, and reduced Aβ deposition in STZ-treated brains using hematoxylin and eosin, Congo red, and Nissl analysis. These effects were evident in the cortical and hippocampal regions. Santonin exhibited strong antioxidant effects, mitigating induced enzyme depletion and oxidative marker elevation. Santonin effectively mitigated STZ-induced Aβ buildup and provided protective effects. Santonin modulated marker expression in STZ-treated brains by reducing the amyloid precursor protein, Tau, toll-like receptor 4, NLRP3, discs large MAGUK scaffold protein 4, and BDNF. Santonin reduces neuroinflammation and neurotrophic signaling in the early stages of AD, which suggests that it may be used as a treatment. However, more research is needed to confirm its effectiveness.},
}

@article {pmid41514416,
year = {2026},
author = {Tian, Q and Liu, M and Zhong, F and Liu, X and Lü, Y},
title = {Lecanemab treatment for mild alzheimer's disease with high risk of cerebral hemorrhage: a case report.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-025-04581-y},
pmid = {41514416},
issn = {1471-2377},
abstract = {BACKGROUND: Lecanemab has been approved for the treatment of mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia based on the efficacy in slowing cognitive decline and preliminary safety data from the phase Ⅲ Clarity AD trial. However, this trial excluded patients with high risk of cerebral hemorrhage, such as individuals with intracranial aneurysms or > 4 microhemorrhages.

CASE PRESENTATION: A 70-year-old male with mild AD, intracranial aneurysm, microhemorrhages, and APOE ε3/ε4 genotype received lecanemab after multidisciplinary evaluation and informed consent. Over six months of intensive monitoring, cognitive function stabilized with no deterioration, daily activities were preserved, microhemorrhages remained stable (with one new small lesion noted at 3 months), and no aneurysm rupture or severe adverse events (including amyloid-related imaging abnormalities) occurred.

CONCLUSIONS: This case suggests that, despite hemorrhage risks, lecanemab may have a manageable risk-benefit profile in selected real-world AD patients under intensive monitoring and multidisciplinary care, with its application beyond clinical trial criteria requiring more nuanced and individualized consideration.},
}

@article {pmid41513640,
year = {2026},
author = {Abdulkhaliq, AA and Kim, B and Almoghrabi, YM and Khan, J and Ajoolabady, A and Ren, J and Bahijri, S and Tuomilehto, J and Borai, A and Pratico, D},
title = {Amyloid-β and Tau in Alzheimer's disease: pathogenesis, mechanisms, and interplay.},
journal = {Cell death & disease},
volume = {17},
number = {1},
pages = {21},
pmid = {41513640},
issn = {2041-4889},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Animals ; Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disease and the most prevalent type of dementia characterized by pathological deposition of amyloid-β plaques/deposits and tau tangles within the brain parenchyma. This progressive ailment is featured by irreversible cognitive impairment and memory loss, often misdiagnosed as the consequence of old age in elderlies. Pathologically, synaptic dysfunction occurs at the early stages and then progresses into neurodegeneration with neuronal cell death in later stages. In this review, we aimed to critically discuss and highlight recent advances in the pathological footprints of amyloid-β and tau in AD. Specifically, we focused our attention on the interplay and synergistic effects of amyloid-β and tau in the pathogenesis of AD. We hope that our paper will provide new insights and perspectives on these pathological features of AD and spark new ideas and directions in AD research and treatment.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
Animals
Brain/metabolism/pathology

@article {pmid41513448,
year = {2025},
author = {Seshagiri, CV and Jackson, BL and Hernandez, M and Leach, JM and Kern, R and Boasso, A and Hajos, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107772},
doi = {10.1002/alz70856_107772},
pmid = {41513448},
issn = {1552-5279},
mesh = {Humans ; *Electroencephalography ; *Alzheimer Disease/physiopathology/therapy/diagnosis ; Male ; Female ; Acoustic Stimulation ; Aged ; Biomarkers ; Photic Stimulation ; *Brain/physiopathology ; *Gamma Rhythm/physiology ; },
abstract = {BACKGROUND: The recent Overture (NCT03556280) clinical trial demonstrated reduced decline in cognitive and functional abilities and reduced brain atrophy in participants with mild to moderate Alzheimer's disease (AD) after 6-months of daily, at-home treatment with Cognito Therapeutics' Spectris™ investigational medical device (Hajós et al. 2024). Spectris uses auditory and visual sensory stimulation to evoke gamma-frequency steady-state oscillations. Here, we evaluate the acute EEG response to auditory and visual stimulation separately and compare with combined audiovisual stimulation.

METHOD: All Overture participants underwent a screening EEG that included measurements of response to Spectris auditory, visual and audiovisual stimulation. Volume and brightness levels were matched for all stimulation within a subject. EEG was collected using gel caps (ANT-Neuro, Philadelphia, PA) from 30 channels (10/20). EEG was preprocessed, visually inspected for a continuous 40s segment with minimal artifacts, and the power spectral density (PSD) was computed at each channel for each modality. The gamma response power was calculated as the ratio of the power at the stimulation frequency [40Hz] to the power in the surrounding gamma frequencies [32-48Hz, exclusive of 39-41Hz]. Statistics reported from ANOVA and Tukey's multiple comparisons test. Average global power reported as mean ± S.E.

RESULT: Of 74 participants randomized, 41 participants had sufficient data quality from all 3 stimulation modalities for analysis. Figure 1 shows maps of the spatial distribution of the gamma response per modality. The number of channels with gamma response above a threshold of 6dB was greatest for audiovisual - 24 vs 21 (auditory) or 22 (visual). The average global power across all electrode channels shows a significant effect of stimulation modality (p < 0.001). Audiovisual simulation [10.73 dB ± 0.56] was higher than auditory [7.39 dB ± 0.52, p < 0.001] and visual [10.01 dB ± 0.52, p = 0.49], but the difference was only significant between audiovisual and auditory. Similar results are seen when looking at Frontal or Occipital channels only.

CONCLUSION: Spectris combined audiovisual stimulation produces the greatest spatial extent and the strongest average global gamma response. Further development and optimization of sensory stimulation therapy may maximize evoked brain responses through modality modifications.},
}

Humans
*Electroencephalography
*Alzheimer Disease/physiopathology/therapy/diagnosis
Male
Female
Acoustic Stimulation
Aged
Biomarkers
Photic Stimulation
*Brain/physiopathology
*Gamma Rhythm/physiology

@article {pmid41513293,
year = {2025},
author = {Chan, T and Rahmouni, N and Zheng, Y and Gonçalves, MP and Therriault, J and Macedo, AC and Trudel, L and Socualaya, KMQ and Hosseini, SA and Hall, BJ and Wang, YT and Aumont, E and Arias, JF and Bezgin, G and Servaes, S and Hopewell, R and Hsiao, C and Vitali, P and Pascoal, TA and Zetterberg, H and Benedet, A and Rosa-Neto, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107774},
doi = {10.1002/alz70856_107774},
pmid = {41513293},
issn = {1552-5279},
mesh = {Humans ; Female ; *Biomarkers/blood/cerebrospinal fluid ; Male ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/blood/diagnostic imaging ; Aged ; *tau Proteins/blood/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Positron-Emission Tomography ; Cohort Studies ; Middle Aged ; Immunoassay ; Quebec ; },
abstract = {BACKGROUND: With the anticipated arrival of disease-modifying treatments for Alzheimer's disease (AD) in Canada, integrating biomarkers into clinical practice is crucial to enhancing diagnostic accuracy and optimizing referrals for treatment. Lumipulse G1200 (Fujirebio) is a fully automated immunoassay instrument that streamlines the analysis of these biomarkers. In this study, we evaluated the diagnostic performance of Lumipulse G1200 plasma and CSF immunoassays in detecting AD pathology within a Quebec population cohort.

METHOD: Plasma and CSF samples of 102 participants from the TRIAD cohort (median age 67 years, 54% female) were analysed. Kruskal-Wallis with post hoc Benjamini-Hochberg false discovery rate (BH) correction compared the levels of biomarkers among the diagnostic groups. Discriminative performance for Aβ ([18]F-NAV4694) and tau ([18]F-MK6240) PET status was assessed using the area under the curve (AUC) of receiver operating characteristic (ROC). Amyloid PET global SUVR > 1.55 and tau PET metaROI SUVR>2.5STD of the young controls determined Aβ and Tau PET positivity, respectively. Spearman's correlation examined the association between plasma p-tau217 and p-tau181 with amyloid and tau PET SUVR.

RESULT: Plasma p-tau181 and p-tau217 were higher in individuals with clinical diagnosis of AD compared to the cognitively unimpaired (CU) or MCI not due to AD (MCI-). Plasma p-tau217 very strongly correlated with both Aβ and tau PET SUVR (ρ=0.805 and 0.797 respectively, p-value<2.2e-16), as compared to plasma p-tau181 (ρ=0.629 and 0.644 respectively, p < 4.097e-10). Both assays identified with comparable high accuracy elevated Aβ pathology (plasma p-tau217, AUC, 0.96, 95% CI: 0.92-1.00; p-tau181, AUC 0.88, CI 0.81- 0.96). However, plasma p-tau217 had higher discriminative performance than p-tau181 for tau PET (p-tau217, AUC 0.99, CI: 0.98-1.00; p-tau181, AUC 0.94, CI 0.89-0.98, DeLong's test p-value<0.01). CSF p-tau181, p-tau181/Aβ42 and Aβ42/40 had excellent discriminative performance for Aβ and tau PET positivity. Moreover, plasma p-tau217 had similar performance as CSF p-tau181 for predicting Aβ and tau PET positivity.

CONCLUSION: Lumipulse G1200 immunoassays showed excellent agreement with amyloid and tau PET. Their ease of use and high diagnostic accuracy make them strong candidates for clinical implementation.},
}

Humans
Female
*Biomarkers/blood/cerebrospinal fluid
Male
*Alzheimer Disease/cerebrospinal fluid/diagnosis/blood/diagnostic imaging
Aged
*tau Proteins/blood/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid/blood
Positron-Emission Tomography
Cohort Studies
Middle Aged
Immunoassay
Quebec

@article {pmid41513238,
year = {2025},
author = {Burns, AP and Fortel, I and Zhan, L and Lazarov, O and Mackin, SR and Demos, AP and Bendlin, BB and Leow, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107724},
doi = {10.1002/alz70856_107724},
pmid = {41513238},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Apolipoprotein E4/genetics ; Magnetic Resonance Imaging ; Biomarkers ; *Alzheimer Disease/genetics/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging/genetics/physiopathology ; *Brain/diagnostic imaging/physiopathology ; Longitudinal Studies ; Aged, 80 and over ; Diffusion Magnetic Resonance Imaging ; Disease Progression ; },
abstract = {BACKGROUND: Excessive neural hyperexcitation has been implicated in early cognitive decline and progression to Alzheimer's disease (AD). Restoring the balance between excitation and inhibition (E/I) with interventions like levetiracetam may offer clinical benefits, particularly for those at heightened risk. Recent cross-sectional studies suggest that female APOE-ε4 carriers may be especially vulnerable to hyperexcitation, but longitudinal evidence remains limited. We therefore investigated whether E/I dysregulation over time differs by sex and APOE-ε4 status in older adults who were cognitively unimpaired at baseline. Figure 1 illustrates the concept of early hyperexcitation preceding AD symptoms.

METHOD: We analyzed multimodal MRI data (resting-state functional MRI and diffusion-weighted imaging) from 106 older adults with at least one cognitively unimpaired scan and three or more longitudinal sessions. Most sessions were rated as clinically unimpaired (CDR = 0), though a subset transitioned to early mild cognitive impairment (CDR = 0.5 or 1). We applied an inverse Ising model regularized by empirical structural connectivity (Figure 2) to derive a whole-brain excitation-inhibition ratio (EIR). Linear mixed modeling tested whether EIR trajectory varied by sex, binary APOE-ε4 status, age at first scan, and time since first scan.

RESULT: A significant three-way interaction (Figure 3) indicated that female APOE-ε4 carriers demonstrate an elevated hyperexcitable EIR trajectory (p = 0.018). Pairwise comparisons further showed higher EIR slopes for female ε4 carriers compared to female non-carriers (p = 0.042). This effect remained significant after adjusting for age, time, and amyloid status, though it was somewhat diminished in participants with fewer longitudinal observations. Regional analyses focusing on default mode and limbic networks found higher baseline excitatory tone in females (p = 0.02), aligning with the global results.

CONCLUSION: These findings provide longitudinal support for a heightened susceptibility to hyperexcitation in female APOE-ε4 carriers, underscoring the importance of sex and genetic risk in preventive and therapeutic strategies for AD. Our multimodal approach integrating structural and functional network data highlights E/I balance as a promising biomarker and treatment target, with levetiracetam representing one potential intervention. Larger studies are needed to confirm how sex- and genotype-specific E/I dysregulation influences dementia risk and therapeutic efficacy.},
}

Humans
Female
Male
Aged
Apolipoprotein E4/genetics
Magnetic Resonance Imaging
Biomarkers
*Alzheimer Disease/genetics/diagnostic imaging
*Cognitive Dysfunction/diagnostic imaging/genetics/physiopathology
*Brain/diagnostic imaging/physiopathology
Longitudinal Studies
Aged, 80 and over
Diffusion Magnetic Resonance Imaging
Disease Progression

@article {pmid41513218,
year = {2025},
author = {Gaona-Partida, PR and Magana-Ramirez, CM and Grill, JD and Gillen, DL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107729},
doi = {10.1002/alz70856_107729},
pmid = {41513218},
issn = {1552-5279},
mesh = {Humans ; Positron-Emission Tomography ; *Biomarkers/metabolism ; *Alzheimer Disease/diagnostic imaging/ethnology/metabolism ; Male ; Female ; Aged ; *Brain/diagnostic imaging/metabolism ; Aged, 80 and over ; Neuroimaging ; Ethnicity ; White People ; },
abstract = {BACKGROUND: In early and preclinical Alzheimer's disease AD clinical trials, amyloid biomarker criteria have resulted in differential ineligibility among racial and ethnic groups. We sought to quantify differences in PET-derived amyloid levels across racial and ethnic groups of similar clinical diagnosis and presumed disease etiology.

METHOD: We utilized data from the Standardized Centralized Alzheimer's and Related Dementias Neuroimaging (SCAN), a newly implemented initiative funded by the National Institute on Aging in conjunction with the National Alzheimer's Coordinating Center (NACC). Our primary outcome was PET-derived amyloid burden using standardized uptake value ratios (SUVRs) shared through the SCAN initiative. Racial and ethnic status were categorized as Non-Hispanic Black (NHB), Non-Hispanic White (NHW), and the remaining participants collated into together (Other), using data obtained from NACC's Uniform Data Set (UDS). We used ordinary least-squares regression to model differences in mean amyloid levels across racial and ethnic groups, with stratification by clinical diagnosis and presumed disease etiology while adjusting for potential confounding factors.

RESULT: We analyzed data on N = 661 NACC participants that had corresponding amyloid PET data available. Table 1 provides basic demographics of the study sample. Figure 1 depicts the distribution of amyloid levels by racial and ethnic group, clinical diagnosis, and presumptive etiology. Table 2 yields the estimated mean differences in SUVR levels by racial and ethnic group stratified by clinical diagnosis and presumptive etiology. After adjustment for potential confounding factors we estimated that NHB participants with cognitive impairment (impaired not MCI or MCI) and probable AD had mean SUVR -0.503 lower than comparable NHW participants (95% CI: (-0.737, -0.270); p-value: <0.001). Among participants with a dementia diagnosis and probable AD the estimated mean difference was -0.242 (95% CI (-0.529,0.045); p-value: 0.099) comparing NHB to NHW.

CONCLUSION: These results add to a growing literature examining amyloid biomarkers across racial and ethnic groups. A limitation of this study is the small sample sizes in several of the groups analyzed. Further research is needed to assess these observed potential differences and the implications to AD trial eligibility and treatment.},
}

Humans
Positron-Emission Tomography
*Biomarkers/metabolism
*Alzheimer Disease/diagnostic imaging/ethnology/metabolism
Male
Female
Aged
*Brain/diagnostic imaging/metabolism
Aged, 80 and over
Neuroimaging
Ethnicity
White People

@article {pmid41513181,
year = {2026},
author = {Vyas, J and Jamenis, AS and Kaku, K and Shah, Y and Miner, KM and Bhatia, TN and Kim, RE and Bai, R and Hamel, E and Leak, RK and Gangjee, A},
title = {Discovery of multitargeting single agents as a novel route to the potential treatment of neurodegenerative diseases.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {133},
number = {},
pages = {130536},
doi = {10.1016/j.bmcl.2026.130536},
pmid = {41513181},
issn = {1464-3405},
abstract = {There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical options will likely require two or more agents with different mechanisms of action. However, drug combinations have significant drawbacks, including overlapping toxicities and unique pharmacokinetic properties, particularly the rate and extent of central nervous system (CNS) penetration. A single agent with multiple mechanisms of action could overcome these drawbacks. We have recently discovered first-in-class novel single agents (compounds 1 and 2) that mildly inhibit clinically important kinases and subtly favor microtubule stability at concentrations that show no evidence of neuronal toxicity in primary neurons, while maintaining their ability to penetrate the CNS in vivo. It is important to note that the effects of these analogs are mild and are predicated on avoiding neurotoxicity. These multitargeting single agents provide a new structural modality with the potential to influence treatments for Parkinson's and Alzheimer's disease and serve as lead compounds for further optimization.},
}

@article {pmid41512280,
year = {2025},
author = {Smith, R and Alkhodair, Y and Yadegari, M and DeMarco, ML},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107634},
doi = {10.1002/alz70856_107634},
pmid = {41512280},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Apolipoprotein E4/blood/genetics ; Male ; Female ; *Alzheimer Disease/genetics/blood/diagnosis ; Aged ; Genotype ; Apolipoproteins E/genetics/blood ; },
abstract = {BACKGROUND: Anti-amyloid therapies (AAT) for Alzheimer's disease are associated with the risk of amyloid-related imaging abnormalities (ARIA). APOE4 homozygotes (E4/E4) have the highest risk, followed by APOE4 carriers (E4), making APOE genotyping essential for risk assessment. While APOE4 allelic status is routinely determined via DNA (e.g., by RT-PCR), recently developed automated immunoassays offer an alternative approach by measuring the apolipoprotein E4 (apoE4) concentration in plasma (i.e., proteotyping). In this study, we evaluated the diagnostic accuracy of an apoE4 proteotyping assay (Fujirebio Lumipulse) and its suitability for ARIA risk assessment.

METHOD: This diagnostic accuracy study included 104 plasma samples from unique individuals with known APOE genotypes determined by RT-PCR: E2/E3 = 8, E3/E3 = 45, E2/E4 = 1, E3/E4 = 44, and E4/E4 = 6. Plasma samples were analyzed using Fujirebio's Lumipulse G1200 system with the Lumipulse G ApoE4 and Pan-ApoE assays. These assays measure apoE4 and total apoE protein concentrations, respectively, and their ratio is used to infer E4 allelic status (non-E4, E4, or E4/E4). The assays were further evaluated for precision, potential interferences, and sample stability across freeze/thaw cycles.

RESULT: The plasma proteotyping assay demonstrated 100% accuracy in distinguishing the presence or absence of an E4 allele compared to RT-PCR. It correctly classified all non-E4 individuals (n = 53), all E4/E4 (n = 6), and 41 of 45 E4 heterozygotes (4 heterozygotes were misclassified as E4/E4). The ApoE4 and Pan-ApoE assays had total coefficients of variation of 8.5% and 4.0%, respectively. No significant interference was observed for hemolysate up to ∼5.25 g/L of hemoglobin or for lipemia up to ∼500 mg/dL of intralipid. Additionally, freeze-thaw testing showed no significant impact on assay performance for up to 4 freeze/thaw cycles.

CONCLUSION: The evaluated plasma apoE4 phenotyping assay demonstrated perfect accuracy in detecting the presence or absence of an E4 allele. However, it did not reliably distinguish E4 heterozygotes from homozygotes, with several heterozygotes misclassified as E4/E4. In the context of AAT treatment eligibility and ARIA risk assessment, proteotyping is an accurate method for both ruling in and out the presence of an E4 allele but E4/E4 results specifically should be confirmed via genotyping.},
}

Humans
*Biomarkers/blood
*Apolipoprotein E4/blood/genetics
Male
Female
*Alzheimer Disease/genetics/blood/diagnosis
Aged
Genotype
Apolipoproteins E/genetics/blood

@article {pmid41512275,
year = {2025},
author = {Aresta, S and Nemni, R and Zanardo, M and Sirabian, G and Capelli, D and Alì, M and Vitali, P and Bertoldo, EG and Fiolo, V and Bonanno, L and Maresca, G and Battista, P and Sardanelli, F and Pizzini, FB and Castiglioni, I and Salvatore, C and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105530},
doi = {10.1002/alz70856_105530},
pmid = {41512275},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers ; *Alzheimer Disease/diagnosis/diagnostic imaging ; Male ; Female ; *Cognitive Dysfunction/diagnosis/diagnostic imaging ; Aged ; Neuropsychological Tests ; Magnetic Resonance Imaging ; Disease Progression ; *Artificial Intelligence ; Neuroimaging ; },
abstract = {BACKGROUND: In 2024, eleven European scientific societies/organizations and one patient advocacy association have defined a patient-centered biomarker-based diagnostic workflow for memory clinics evaluating neurocognitive disorders. This study aimed to evaluate the clinical performance of an Artificial Intelligence (AI)-tool applied to neuropsychological assessment and MRI for supporting the staging, clinical profiling, diagnosis, causal hypothesis, and progression of subjects at risk of Alzheimer's disease (AD) following the above-mentioned intersocietal recommendations.

METHOD: This observational, multicentric study enrolled 796 subjects: 705 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, 35 from Centro Diagnostico Italiano (Italy), 26 from IRCCS Policlinico San Donato (Italy), and 30 from IRCCS Bonino Pulejo (Italy). Participants were clinically staged as healthy subjects (HS), subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or AD-dementia at baseline and 24-month follow-up. Patients were clinically profiled into AD clinical syndromes based on cognitive characteristics and structural neuroimaging findings. First-line biomarkers were also measured. The AI-based software TRACE4AD™ automatically processed neuroimaging and neuropsychological test data to extract cognitive and structural findings. The tool staged subjects as HS/SCI, MCI, or moderate-to-severe-dementia (MSD), profiled the causal hypothesis, and predicted conversion risk to AD-dementia. Agreement between AI and human staging was assessed using Cohen's kappa. AI-performance was evaluated by sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under curve (AUC), and accuracy.

RESULT: For the staging classification the inter-rater AI-humans agreement was substantial for both HS/SCI vs. rest (Cohen's κ = 0.81) and MCI (κ = 0.70) classification, almost perfect for MSD vs. rest (κ = 0.90) classification. For the causal hypothesis classification, the AI performance vs. biomarker-based diagnosis was: PPV 91%, NPV 100%, and accuracy 91%. For the binary classification of progression to AD-dementia at 24-month, the AI performance was: sensitivity 89%, specificity 82%, accuracy 85%, and AUC 83%.

CONCLUSION: The AI-tool demonstrated its usefulness in supporting the clinical treatment of AD patients by assisting with staging, clinical profiling, diagnosis, hypothesis generation for underlying causes, and predicting the risk of progression to AD-related dementia within 24 months.},
}

Humans
*Biomarkers
*Alzheimer Disease/diagnosis/diagnostic imaging
Male
Female
*Cognitive Dysfunction/diagnosis/diagnostic imaging
Aged
Neuropsychological Tests
Magnetic Resonance Imaging
Disease Progression
*Artificial Intelligence
Neuroimaging

@article {pmid41512235,
year = {2025},
author = {Singh, A and Denkinger, MN and Dieckhoff, K and Liu, J and Serrano, GE and Beach, TG and Leuzy, A and Atri, A and Reiman, EM and Ashton, NJ},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105227},
doi = {10.1002/alz70856_105227},
pmid = {41512235},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Cerebral Amyloid Angiopathy/blood/diagnosis ; Aged ; *Alzheimer Disease/blood ; Aged, 80 and over ; },
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels leading to increased risk of microbleeds, intracerebral hemorrhages, and progressive cognitive decline. It is estimated that up to 90% of individuals with Alzheimer's disease (AD) exhibit some degree of CAA. Notably, CAA has been identified as a major contributor to the risk of Amyloid-Related Imaging Abnormalities (ARIA), particularly in patients undergoing treatment with anti-amyloid therapies. The use of blood-based biomarkers to accurately detect and assess the severity of CAA is crucial for tailoring treatment plans while reducing the risk of adverse effects.

METHOD: We employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA™) central nervous system panel for an exploratory biomarker quantification in plasma of patients with CAA or no-CAA (presence of cerebral amyloidotic blood vessels) utilizing samples from the Banner Health Brain and Body Donation Program (BBDP) We evaluated the differential protein expression between groups using a linear model. This model was adjusted for age, sex, APOE e4 carrier status and the presence of Alzheimer's amyloid plaque load (AD-status).

RESULT: We selected 251 participants (age: 85±8.2) from the BBDP cohort with a plasma sample taken < 5 years (1.45±1.26) prior to death. At post-mortem each case was classified as CAA+ (n = 140) or CAA- (n = 111). NULISA™ identified several novel proteomic biomarkers which were up-regulated (CRP, IL4, SAA1), and down-regulated (CCL11, PDLIM5, NPY and GDNF) in CAA pathology carriers (Figure 1). We further performed receiver operating characteristic (ROC) curve analysis comparing models and found that a model including age, sex, AD-status, APOE e4 status, CRP and CCL11 had an area under the curve (AUC) of 0.87 (95%CI, 0.83-0.92) to identify the presence of CAA at post-mortem (Figure 2).

CONCLUSION: Blood-based biomarkers capable of identifying CAA could play an important role in improving treatment outcomes by highlighting ARIA risk prior to treatment initiation. We found that plasma proteins related to inflammation, blood brain barrier dysfunction and cytoskeletal stability were significantly changed in participants with confirmed CAA. Further work will be required to replicate these findings in an independent dataset.},
}

Humans
*Biomarkers/blood
Male
Female
*Cerebral Amyloid Angiopathy/blood/diagnosis
Aged
*Alzheimer Disease/blood
Aged, 80 and over

@article {pmid41512156,
year = {2025},
author = {Geraci, J and Searls, E and Qorri, B and Ho, K and Burk, A and Tsay, M and Cumbaa, C and Pani, L and Alphs, L and Alosco, ML and Mez, J and Au, R},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107581},
doi = {10.1002/alz70856_107581},
pmid = {41512156},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis/physiopathology ; *Alzheimer Disease/diagnosis ; Aged ; *Biomarkers ; Neuropsychological Tests ; Sleep/physiology ; Machine Learning ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) precision medicine will advance through the application of two key technological advances: 1) digital technologies that can more deeply characterize clinically relevant symptoms and 2) machine learning (ML) approaches the can classify subgroups with shared characteristics that could align with specific treatment plants. This study leverages a digital data collection platform for enhanced characterization and NetraAI, an artificial intelligence (AI) platform to analyze multimodal data to differentiate causal and non-causal subpopulations within a cohort and integrates a "No Call" system to exclude ambiguous data points.

METHOD: We analyzed data from 98 Boston University Alzheimer's Disease Research Center participants and 453 variables derived from digital tasks administered over two months. Eight participants were clinically diagnosed as mild cognitive impairment. Digital measures included sleep metrics (57 measures), clinical scales (324 measures), and cognitive performance assessments (72 GoNoGo and Code Substitution measures). Of the 98 subjects, 81 were cognitively unimpaired and 17 transitioned to MCI during the course of study enrollment.

RESULT: Sleep-derived metrics, including 3% and 4% desaturation thresholds (p = 4×10[-5], p = 7×10[-5]), and periodicity (eLFCnb) (p = 0.008) characterized one population of 8 participants, 7 of whom had been diagnosed with MCI. Incorporating maximum heart rate, another sleep metric, distinguished another subpopulation of 8 subjects (6/8 were diagnosed MCI) with elevated heart rate (p = 10[-10]). We examined 81 cognitively intact (e.g., non-transitioners; Class 0) and 17 MCI transitioners (Class 1) related to Go/No-Go and Code Substitution tasks. Go/No-Go Inter-Trial Intervals (ITI), REM sleep percentage, and maximum apnea duration were key predictors. Shorter, more stable ITI times (inter-trial intervals between tasks), higher REM sleep percentage, and shorter apnea durations were strongly correlated with non-transitioners. A 10-fold cross-validation yielded an average accuracy of 80.89%.

CONCLUSION: Our findings present an ongoing effort on the potential of explainable AI to validate digital measures to identify those with MCI. While the current model effectively identifies prevalent non-transitioners, it remains limited in identifying prevalent transitioners. Future research will focus on refining model sensitivity and balancing classification performance.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis/physiopathology
*Alzheimer Disease/diagnosis
Aged
*Biomarkers
Neuropsychological Tests
Sleep/physiology
Machine Learning
Aged, 80 and over

@article {pmid41512123,
year = {2025},
author = {Paez, A and Dogaheh, SB and Gillman, SO and Carnes, A and Dakterzada, F and Barbe, F and Piñol-Ripoll, G and Dang-Vu, TT},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107617},
doi = {10.1002/alz70856_107617},
pmid = {41512123},
issn = {1552-5279},
mesh = {Humans ; Female ; *Biomarkers/cerebrospinal fluid ; Male ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/physiopathology ; Aged ; Chitinase-3-Like Protein 1/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Polysomnography ; Peptide Fragments/cerebrospinal fluid ; Neuropsychological Tests ; Prospective Studies ; Neurogranin/cerebrospinal fluid ; Aged, 80 and over ; Sleep/physiology ; },
abstract = {BACKGROUND: Sleep is essential for brain-health, including clearance of β-amyloid (Aβ), tau, and otherpromising diagnostic markers of neurodegeneration and progression in Alzheimer's Disease (AD): cerebrospinal fluid neurofilament-light chain (NfL), neurogranin-36 (NG-36), and Chitinase-3-like protein-1 (YKL-40). However, it remains unclear which sleep characteristics predict these biomarkers or whether the biomarkers predict cognitive or neuropsychiatric decline after AD onset.

METHODS: Using data from a prospective cohort study of mild-to-moderate AD (n = 60, 30-female, mean age 74.7), we analysed non-rapid eye-movement sleep spindles and slow oscillations (SO) at baseline and their associations with baseline NfL, YKl-40, NG-36, NfL/Aβ42, YKl-40/Aβ42, and whether these biomarkers predict cognition and mental health from baseline to three-years follow-up. Participants underwent baseline polysomnography (PSG) and cerebrospinal fluid draws for amyloid and tau, and neuropsychological assessment at baseline, 12, 24 and 36 months with the Mini-Mental Status Examination (MMSE), and the Alzheimer's Disease AssessmentScale-Cognitive Subscale (ADAS-Cog) and Neuropsychiatric Inventory (NPI) at baseline and 12 months. Spindle and SO detection were performed using in-house, open-source software packages developed at Concordia University. Associations between SO and spindle characteristics (duration, density, power, amplitude), biomarkers, and cognition from baseline to 36 months were investigated with false discovery rate-adjusted robust regression controlling for age, sex, apnea-hypopnea index.

RESULTS: We found previously unreported associations between spindle and SO characteristics, NfL, YKl-40, NG-36, NfL/Aβ42 (β=-.0029, p = 0.001), YKl-40/Aβ42 (β=0.0004, p = 0.003) and cognition in persons with AD. These biomarkers predicted worse cognitive performance (higher ADAS-cog [β=2.28, p = 0.004], lower MMSE scores [β= -2.42, p = 0.01]) from baseline to 36-months, and a significant increase in neuropsychiatric symptom severity (NPI β=16.93 p <0.001). NfL/Aβ42 mediated the effects of spindle activity on cognitive performance on the ADAS-cog (p =  0.041) and MMSE (p = 0.0019). Biomarkers also moderated the relationships between spindle and SO activity on cognition, and spindles and SO moderated the relationships between these biomarkers and cognition.

CONCLUSIONS: Our novel findings demonstrate that spindle and SO activity are associated with NfL, YKl-40, and NG-36, and cognitive decline, constituting predictive, non-invasive biomarkers of neurodegeneration, cognition, and mental health in AD. They may thus provide novel treatment targets for delaying AD progression.},
}

Humans
Female
*Biomarkers/cerebrospinal fluid
Male
*Alzheimer Disease/cerebrospinal fluid/diagnosis/physiopathology
Aged
Chitinase-3-Like Protein 1/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Neurofilament Proteins/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Polysomnography
Peptide Fragments/cerebrospinal fluid
Neuropsychological Tests
Prospective Studies
Neurogranin/cerebrospinal fluid
Aged, 80 and over
Sleep/physiology

@article {pmid41511881,
year = {2025},
author = {Brodman, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107562},
doi = {10.1002/alz70856_107562},
pmid = {41511881},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Amyloid beta-Peptides/blood ; Male ; *Alzheimer Disease/diagnostic imaging/blood/pathology/diagnosis ; Female ; *tau Proteins/blood ; Positron-Emission Tomography ; Aged ; Glial Fibrillary Acidic Protein/blood ; Brain/diagnostic imaging/pathology ; },
abstract = {BACKGROUND: Plasma biomarkers are critical for early detection and treatment of Alzheimer's disease (AD). We assessed plasma biomarker association and classification capacity against neuroimaging measures.

METHOD: In the racially diverse Human Connectome Project (HCP; n = 218, 15% Aβ-PET-positive) Aβ-PET and cortical thickness (neurodegeneration) were related to plasma biomarkers (p-tau181, p-tau217 [Janssen and ALZpath], p-tau231, GFAP, NfL, Aβ42/Aβ40).

RESULT: Plasma p-tau217 accurately identified abnormal Aβ-PET (: AUC=0.9145, 95% CI=[0.8367, 0.9923]) followed by GFAP and Aβ42/40 ratio (GFAP (AUC=0.8529, 95% CI = [0.7485, 0.9573], Aβ42/40 (AUC = 0.7962, 95% CI = [0.6581, 0.9346]). All biomarkers performed poorly to identify cortical thickness, but were increased according to combined Aβ-PET-neurodegeneration profiles. Correlations of p-tau217, p-tau181, and Aβ42/40 with Aβ-PET were stronger in self-identified non-Hispanic Whites vs. Black/African Americans.

CONCLUSION: Plasma biomarkers identify brain Aβ pathology in the community. However, consideration of potential racial/ethnic differences in brain-to-blood biomarker correlations should be critically examined and addressed to enable widespread cross-population applications.},
}

Humans
*Biomarkers/blood
*Amyloid beta-Peptides/blood
Male
*Alzheimer Disease/diagnostic imaging/blood/pathology/diagnosis
Female
*tau Proteins/blood
Positron-Emission Tomography
Aged
Glial Fibrillary Acidic Protein/blood
Brain/diagnostic imaging/pathology

@article {pmid41511604,
year = {2026},
author = {Babaker, MA and Alazabi, NI and Yousef, EM and Haredy, SA and Algohary, AM and Mansour, DF and Ahmed-Farid, OA},
title = {Taurine Mitigates Spironolactone-Induced Hyperkalemia and Cognitive Dysfunction: A Biochemical and Histological Study in a Rat Model.},
journal = {Applied biochemistry and biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s12010-025-05513-9},
pmid = {41511604},
issn = {1559-0291},
abstract = {Spironolactone (SPR), a widely used potassium-sparing diuretic, frequently causes hyperkalemia, leading to significant cardiovascular and neurological complications. Taurine, a semi-essential amino acid with known antioxidant and neuroprotective effects, was hypothesized to mitigate these adverse effects. This study investigated taurine's efficacy against SPR-induced hyperkalemia and associated cognitive dysfunction in a rat model. Adult male Sprague-Dawley rats were treated for four weeks with SPR, SPR + galantamine (an AChE inhibitor widely used in the treatment of Alzheimer's disease), or SPR + varying concentrations of taurine, followed by assessment of cognitive, biochemical, and histopathological alterations. SPR administration significantly increased serum potassium levels (~7.5 mEq/L), induced cognitive deficits, disrupted neurotransmitter balance (e.g., altered GABA and glutamate levels), and caused reactive astrocytic swelling in key brain regions. Taurine demonstrated a dose-dependent protective effect against SPR-induced neurotoxicity by mitigating hyperkalemia and associated cognitive impairments. Biochemically, taurine restored neurotransmitter balance by increasing GABA and reducing the excitotoxic glutamate levels. Histological analysis further confirmed taurine's neuroprotective effects, showing preserved cortical structures and reduced astrogliosis, especially at the highest concentration (5%). Our correlation analysis reveals complex regulatory mechanisms underlying neurotransmitter balance in the brain. These findings suggest taurine as a promising therapeutic agent for alleviating SPR-induced neurological side effects. Further studies are needed to explore taurine's long-term effects and clinical applications in managing hyperkalemia-related cognitive dysfunctions.},
}

@article {pmid41511339,
year = {2025},
author = {Yu, H and Josi, RR and Khanna, A and Khismatullin, DB},
title = {Low-Density Lipoproteins Induce a Pro-Inflammatory, Chemotactic Mox-like Phenotype in THP-1-Derived Human Macrophages.},
journal = {Cells},
volume = {15},
number = {1},
pages = {},
pmid = {41511339},
issn = {2073-4409},
support = {1R01HL127092-01A1/NH/NIH HHS/United States ; },
mesh = {Humans ; *Lipoproteins, LDL/pharmacology ; *Macrophages/metabolism/drug effects ; *Chemotaxis/drug effects ; Phenotype ; THP-1 Cells ; *Inflammation/pathology/metabolism ; Mast Cells/metabolism/drug effects ; Interleukin-6/metabolism ; Cytokines/metabolism ; Cell Differentiation/drug effects ; },
abstract = {Murine macrophages exposed to oxidized low-density lipoprotein (oxLDL) polarize into a distinct Mox phenotype characterized by impaired phagocytic and chemotactic function. Although implicated in atherosclerosis, this phenotype has not been confirmed in human macrophages. Drawing parallels to human tumor-associated macrophages, and in contrast to the murine cell response, we hypothesize that LDL/oxLDL induces a hybrid Mox-like state in human macrophages, marked by the simultaneous secretion of pro-inflammatory cytokines and anti-inflammatory factors, potentially exacerbating vascular inflammation and atherogenesis. To test this, THP-1 human monocytes were differentiated into resting macrophages, then polarized into M1-like and M2-like phenotypes, followed by treatment with native LDL, oxLDL, IL-6, or their combinations. ELISA results showed that oxLDL or LDL with IL-6 polarized resting and M1-like macrophages into a Mox-like phenotype that secreted TNF-α and TGF-β1 at levels comparable to M1- and M2-like cells, respectively. The pro-inflammatory nature of Mox-like macrophages was supported by increased THP-1 adhesion to vascular endothelial cells exposed to the macrophage-conditioned media. In microfluidic assays, LUVA human mast cells migrated toward media from Mox-like macrophages, indicating enhanced chemotaxis. In summary, the pro-inflammatory Mox-like state is triggered in human macrophages by oxLDL or LDL combined with IL-6, a key regulator of the inflammatory acute-phase response. Unlike in murine cells, this state is marked by high chemotactic activity driven by TGF-β1 secretion, which promotes mast cell recruitment and contributes to atherosclerotic plaque development and Alzheimer's disease.},
}

Humans
*Lipoproteins, LDL/pharmacology
*Macrophages/metabolism/drug effects
*Chemotaxis/drug effects
Phenotype
THP-1 Cells
*Inflammation/pathology/metabolism
Mast Cells/metabolism/drug effects
Interleukin-6/metabolism
Cytokines/metabolism
Cell Differentiation/drug effects

@article {pmid41511284,
year = {2025},
author = {Valer, MAA and Ferrari-Souza, JP and Barcellos, LFB and de Jesus Vanni, IJ and Bieger, A and Leffa, DT and Lussier, FZ and Brum, WS and Aguzzoli, C and Corin, A and De Bastiani, M and Carello-Collar, G and Borelli, WV and Rahmouni, N and Therriault, J and Trudel, L and Macedo, AC and Ferreira, PCL and Povala, G and Bellaver, B and Souza, DO and Rosa-Neto, P and Pascoal, TA and Zimmer, ER},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107452},
doi = {10.1002/alz70856_107452},
pmid = {41511284},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; Aged ; Biomarkers/metabolism ; Longitudinal Studies ; Aged, 80 and over ; Disease Progression ; *Brain/diagnostic imaging/metabolism ; Aniline Compounds ; Prognosis ; Cohort Studies ; Carbolines ; Ethylene Glycols ; },
abstract = {BACKGROUND: Recent revised criteria for Alzheimer's disease (AD) emphasize the potential utility of imaging biomarkers in disease staging. Although promising, the practical applicability of staging schemes requires further investigation. In this study, amyloid-β (Aβ) and tau positron emission tomography (PET) were used to evaluate the prognostic performance of the imaging-based biological staging criteria in cognitively unimpaired (CU) individuals.

METHOD: This longitudinal analysis involved 662 CU individuals: 467 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and 195 individuals from the Anti-Amyloid Treatment in Asymptomatic AD (A4) study placebo group. In the ADNI cohort, Aβ positivity (A+) was defined as standardized uptake value ratios (SUVR) >1.11 for [18F]Florbetapir and >1.08 for [18F]Florbetaben. In A4, Aβ positivity was established via visual reading. Tau tangles were assessed using [18F]Flortaucipir for both cohorts, with positivity defined as 2.0 standard deviations (SD) above the mean SUVR of Aβ-negative CU reference groups (ADNI:n = 352; LEARN A4 substudy: n = 55). These tau PET cutoffs, derived from the medial temporal lobe (MTL) and neocortex (NEO) regions, were applied to classify individuals as TMTL+ and TNEO+. We used Kaplan-Meier curves and Cox proportional hazard models to evaluate the 4-year risk of clinical progression (i.e., one point increase in the Clinical Dementia Rating - Sum of Boxes) according to imaging-based baseline groups.

RESULT: The mean (SD) age of the study population was 72.1 (6.8) years, and 264 (39.9%) were men (Table 1). Kaplan-Meier curves demonstrated that the A+TNEO+ group presented a separate survival probability curve compared to the other groups (Figure 1A). Cox proportional-hazards models corroborated the greatest risk of clinical progression in the A+TNEO+ (HR = 9.98) group, followed by the A+TMTL+ (HR = 4.29) and A+T- (HR = 2.31) groups, in comparison to the reference group (A-T-; Figure 1B).

CONCLUSION: The integration of Aβ and tau PET imaging provides critical prognostic information in early disease stages, with neocortical tau deposition performing as a robust predictor of clinical progression. These findings reinforce the utility of imaging biomarkers for AD staging and prognosis, highlighting that the topography of tau tangle accumulation is a key factor in enhancing risk stratification of individuals with preclinical AD.},
}

Humans
Male
Female
Positron-Emission Tomography
*Alzheimer Disease/diagnostic imaging/metabolism
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism
Aged
Biomarkers/metabolism
Longitudinal Studies
Aged, 80 and over
Disease Progression
*Brain/diagnostic imaging/metabolism
Aniline Compounds
Prognosis
Cohort Studies
Carbolines
Ethylene Glycols

@article {pmid41511187,
year = {2025},
author = {Sun, X and Badachhape, AA and Reid, TE and Chin, J and Shulman, JM and Annapragada, A and Lowe, H and Toyang, N and Tanifum, E},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107465},
doi = {10.1002/alz70856_107465},
pmid = {41511187},
issn = {1552-5279},
mesh = {Animals ; Mice ; *Microglia/metabolism/pathology ; Biomarkers/metabolism ; Magnetic Resonance Imaging/methods ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Humans ; Disease Models, Animal ; Mice, Transgenic ; Liposomes ; Brain/metabolism/pathology/diagnostic imaging ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; },
abstract = {BACKGROUND: Microglia-mediated neuroinflammation plays a pivotal role in the initiation and propagation of pathological markers of neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). CSF1-R signaling mediates microglial activation, proliferation, and survival; both CSF1-R upregulation and increased proliferation of microglia have been observed in AD patients. Imaging technologies that effectively profile reactive microgliosis in vivo have the potential to be diagnostic tools, facilitate patient stratification in clinical trials, and monitor treatment. There is currently no clinically approved tool to profile reactive microgliosis in vivo. We present a novel molecular imaging technique for neuroinflammation by targeting CSF1-R with MRI sensitive liposomes.

METHOD: Liposomes with DSPE-PEG-Caflanone as the targeting moiety, and Gd(III) DSPE-DOTA as the MRI contrast source were formulated using standard protocols. Caflanone is a potent CSF1-R ligand. In vitro nanoparticle cell uptake studies and blocking experiments with free Caflanone employing both human and mouse microglia cell lines were used to establish receptor-mediated internalization of the agent. Two AD mouse models (APP/PSEN1 and P301S) and one PD mouse model (A53TαS Tg) were used in in vivo MRI studies. Controls included wild type (WT) litter mates injected with the same agent. Mice were pre-scanned to establish a baseline followed by injection of the agent. Post-contrast scans were obtained at 4 days post-injection, followed by euthanasia, and brain removal for ex vivo immunohistochemical analysis.

RESULT: As shown in Figure 1, in vitro cell assays showed internalization of the Caflanone labeled nanoparticles within 1.5 hours of exposure. Coincubation with increasing concentrations of free Caflanone resulted in diminished particle uptake at high concentrations of the free ligand. In vivo MRI demonstrated increased brain retention of the nanoparticles in transgenic mice compared to controls. Ex-vivo immunohistochemical analysis showed the nanoparticles in the cytosolic compartment of IBA1 reactive cells surrounding amyloid-β (Aβ) plaques in the APP/PSEN1 mouse model.

CONCLUSION: Results demonstrate precision delivery of Caflanone labeled liposomes bearing an MRI diagnostic payload to activated microglia in three different mouse models of neurodegenerative disorders. These nanoparticles can also deliver a therapeutic payload with similar precision, opening a new frontier for the development of both diagnostics and therapeutics for neuroinflammation.},
}

Animals
Mice
*Microglia/metabolism/pathology
Biomarkers/metabolism
Magnetic Resonance Imaging/methods
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Humans
Disease Models, Animal
Mice, Transgenic
Liposomes
Brain/metabolism/pathology/diagnostic imaging
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism

@article {pmid41510854,
year = {2026},
author = {Tyagi, S and Murali, N and Singh, SK and Babtiwale, SR and Padhi, BK and Lakshmi, NRA and Gandhi, AP},
title = {A Systematic Review to Evaluate the Effect of Neflamapimod on Cognitive Function and Progression of Dementia.},
journal = {Neurology India},
volume = {74},
number = {1},
pages = {12-19},
doi = {10.4103/neurol-india.Neurol-India-D-25-00227},
pmid = {41510854},
issn = {1998-4022},
mesh = {Humans ; *Cognition/drug effects ; Disease Progression ; *Dementia/drug therapy ; *Alzheimer Disease/drug therapy ; *Lewy Body Disease/drug therapy ; },
abstract = {Treatment options for dementia mainly comprise of symptomatic treatment, as no disease-modifying therapy currently exists that directly reduces the pathology. This systematic review assessed the effectiveness of neflamapimod (VX-745), a p38α kinase inhibitor, as a therapeutic agent for treating dementia, including Alzheimer's disease (AD) and Lewy Body Dementia (LBD). The systematic review evaluated the therapeutic effect of neflamapimod on dementia. Five electronic databases were included in the systematic review: PubMed, Embase, ProQuest, Cochrane Library, and Web of Science, which were searched until May 5, 2024. Two independent reviewers conducted title and abstract screening, followed by full-text review and data extraction, with disagreements resolved by a third reviewer. The risk of bias in the included studies was assessed using the ROB 2.0 tool. PROSPERO Registration ID: CRD42024542377. The review identified clinical results, biomarker effects, and mechanistic insights from two key trials. Due to the inclusion of only two eligible studies with varying methodologies and outcome measures, a meta-analysis could not be performed. While the primary cognitive outcomes, such as "neuropsychological test battery (NTB)" and "Hopkins Verbal Learning Test-Revised (HVLT-R)" were not statistically different, episodic memory, executive function, attention, gait dysfunction, and motor issues showed improvements, especially in patients with elevated plasma tau181, a marker for AD pathology. Biomarker analysis also indicated a statistically significant reduction in cerebrospinal fluid (CSF) tau and phosphorylated tau biomarkers, which are closely related to neuroinflammation and synaptic impairment in dementia. The findings of the current review suggested that while the cognitive effects of neflamapimod remain uncertain, its ability to influence disease-specific biomarkers makes it a potential drug to be used in dementia. This review connects biological and clinical outcomes, paving the way for future advancements in dementia treatment strategies.},
}

Humans
*Cognition/drug effects
Disease Progression
*Dementia/drug therapy
*Alzheimer Disease/drug therapy
*Lewy Body Disease/drug therapy

@article {pmid41510732,
year = {2026},
author = {Adhikari, B and Venkatesh, DN and Puri, V and Sharma, A},
title = {Therapeutic Implications of Nutraceutical Nanotechnology for the Treatment of Chronic Diseases.},
journal = {Current drug metabolism},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892002415344251122122358},
pmid = {41510732},
issn = {1875-5453},
abstract = {Nanotechnology possesses therapeutic value in managing chronic disease, but it has limitations like as solubility, stability, and targeted delivery in clinical applications. The review explores how nanotechnology-based delivery systems improve the efficacy, bioavailability, and targeted actions of nutraceutical compounds. Health benefits, sustainable nanotechnology, market size, and growth forecasts have shown positive results in this industry over the last two decades. The disease-like respiratory, diabetes, Alzheimer's and Parkinson's, and breast cancer top focused sectors for this nutraceuticals sector. Most literature has been collected from 2020-2025 using PubMed, Scopus, Google Scholar, and Web of Science. The different criteria included preclinical, clinical, and nanotechnology-integrated nutraceutical studies. The liposomes, dendrimers, nanoemulsions, and polymeric nanoparticles significantly enhance the stability and delivery of key bioactive as example like curcumin, resveratrol, and omega-3. Early-stage clinical trials show promise for diseases like Alzheimer's, diabetes, and cancer. Nanotechnology is the reshaping of nutraceutical therapy, through regulatory, toxicology, and large-scale validation gaps persist. Future work must focus on green synthesis, long-term safety, and harmonized approval pathways. Despite this, the industry still needs collaboration between academic researchers, scientists, and regulatory bodies to start the next generation of clinical trials and treatments that can reduce the risk of diseases and death in the future.},
}

@article {pmid41510728,
year = {2026},
author = {González-Jiménez, KA and Herrera-Mayorga, EV and Paredes Sánchez, FA and Niño-García, N and Torres-Castillo, JA and Martínez-Padrón, HY and Sánchez-Sánchez, M},
title = {New Drug Therapies Against Targeting Neurodegenerative Diseases: A Comprehensive Review.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249397580251117044621},
pmid = {41510728},
issn = {1875-6166},
abstract = {Neurodegenerative diseases encompass well-characterized behavioral, cognitive, and movement disorders that affect older people, impacting all facets of daily life. In Alzheimer's disease, specific antibodies targeting the β-amyloid protein (aducanumab, lecanemab, and others) are gaining special interest due to the approval of the first particular drugs against this disease. In Parkinson's disease, most drugs were approved several decades ago; however, new Phase II clinical trials point to monoclonal antibodies as a promising approach, and the report of alkaloids also suggests various therapeutic targets against this disease. Pick's disease has a low prevalence; currently, no drugs are approved by government agencies. However, thanks to molecular tools, it has been possible to elucidate therapeutic targets implicated in the appearance of the disease. α-synuclein is the main therapeutic target in Lewy body disease; most of the reported molecules are in clinical Phases I and II. Additionally, drug repositioning may emerge as a viable option in the search for effective treatments against this disease. In amyotrophic lateral sclerosis, the appearance of newly approved drugs such as tofersen and edaravone, and some others in clinical Phase II (bosutinib), opens a new era in the understanding and treatment of this condition. Altered emotions and progressive damage in some brain regions characterize schizophrenia and vascular dementia. Combinations of tricyclic drugs are a trend that aims to increase the cognitive performance of patients with schizophrenia. In vascular dementia, numerous in vivo trials with molecules of different natures (flavonoids and lactones) have yielded positive results, delaying the progression of the disease. This review examines recent reports on molecules evaluated in vivo and in vitro models of the primary neurodegenerative diseases.},
}

@article {pmid41510718,
year = {2026},
author = {Prabakaran, A and Sivaperuman, A and Natarajan, R and Nagarajan, NC and Solomon, VR},
title = {Innovative Approaches to Alzheimer's Treatment: Utilizing Tacrine Hybrids to Inhibit Amyloid Beta Aggregation as a Strategic Focus.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575422492251116190843},
pmid = {41510718},
issn = {1875-5607},
abstract = {Alzheimer's disease (AD) is a complex and progressive brain disorder marked by memory loss, cognitive decline, and behavioral changes. One of its defining features is the build-up of amyloid plaques, clumps of β-amyloid (Aβ) peptides, in the brain, along with the formation of neurofibrillary tangles. These Aβ peptides are generated when the amyloid precursor protein (APP) is cleaved by enzymes, with β-secretase (BACE1) playing a key role in the first step of this process. Because BACE1 starts the cascade that leads to harmful Aβ build-up, it has become an important target in the search for effective Alzheimer's treatments. As Aβ accumulates in neurons, it disrupts communication between brain cells and triggers oxidative stress, which worsens damage and accelerates disease progression. This is often exacerbated by imbalances in metal ions, such as copper and iron. While tacrine, an early acetylcholinesterase inhibitor, has shown benefits in managing AD symptoms, its limitations have led researchers to explore improved versions. One promising direction is the development of tacrine-based hybrid molecules. By combining tacrine with other chemical groups that have anti-β-amyloid (Aβ) effects, antioxidant properties, and metal-chelating properties, scientists aim to create compounds that target multiple aspects of the disease simultaneously. This review examines the emerging potential of tacrine hybrids, particularly their capacity to inhibit BACE1 and prevent Aβ aggregation, providing new hope for more effective and disease-modifying therapies for Alzheimer's disease.},
}

@article {pmid41510716,
year = {2026},
author = {Bano, A and Khan, AA and Kushwaha, SP and -, A and Zaidi, SMH and Misbahul Hasan, S and Fatima, A},
title = {Indole Scaffolds in Neurological Therapeutics: Synthesis, Structure-Activity Relationships and Drug-Receptor Interactions.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575415521251021091530},
pmid = {41510716},
issn = {1875-5607},
abstract = {INTRODUCTION: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.

METHODS: A detailed literature survey was conducted using databases such as Google Scholar, Elsevier, PubMed, ACS, PubChem, ScienceDirect, and RSC to understand the structural modifications of indole derivatives and their therapeutic potential. Both research and review articles related to indole- based compounds were thoroughly studied to prepare this review article.

RESULTS: There are over 40 FDA-approved drugs containing an indole nucleus used to treat various diseases, underscoring its potential in neurotherapeutics. This review highlights innovative synthetic strategies, including green chemistry approaches, that improve the drug-likeness and bioavailability of indole derivatives. Indole continues to be an indispensable scaffold in the development of novel therapeutics aimed at addressing the growing burden of neurological disorders.

DISCUSSION: This review aims to provide a comprehensive analysis of the therapeutic potential of indole-based compounds for the treatment of neurological disorders. However, challenges like blood-brain barrier permeability and long-term safety must be addressed for clinical success. Nonetheless, this review will help in designing and developing newer indole-based molecules in the discovery of neurological drug development.

CONCLUSION: Due to its broad spectrum of biological activities and favorable pharmacokinetic properties, indole is an impressive scaffold for the treatment of various neurological disorders. Indole demonstrates remarkable therapeutic potential against a range of central nervous system-related conditions, including Alzheimer's disease, epilepsy, migraine, stroke, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and Huntington's disease.},
}

@article {pmid41510572,
year = {2026},
author = {Tang, C and Han, K and Wen, X and Zhang, J and Sun, W and Yue, X and Shi, L and Liu, Z and Zhao, J and Yan, C and Liu, M and Yao, Z and Kong, Z and Liu, Y and Fu, Z and Zhao, X and Yang, Z and Han, M and Chen, C and Xing, Z and Zhou, X and Yang, F and Zhang, Y and Jiang, X},
title = {Synthetic Disaggregators Enhance Central-Peripheral Amyloid-β Clearance in Alzheimer's Disease.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e20002},
doi = {10.1002/adma.202520002},
pmid = {41510572},
issn = {1521-4095},
support = {2024YFA0918400//National Key Research and Development Program of China/ ; 82350125//National Natural Science Foundation of China/ ; 82425056//National Natural Science Foundation of China/ ; 82173763//National Natural Science Foundation of China/ ; 82303810//National Natural Science Foundation of China/ ; ZR2022ZD18//Fundamental Research Funds of Shandong Province/ ; ZR2023QH224//Natural Science Foundation of Shandong Province/ ; 2022M721967//China Postdoctoral Science Foundation/ ; 2024T170524//China Postdoctoral Science Foundation/ ; SYS202202//Shandong Provincial Laboratory Project/ ; NO.tsqnz20221165//Taishan Scholar Foundation of Shandong Province/ ; 2025CXPT177//Key R&D Program of Shandong Province/ ; 2025CXPT177//Key R&D Program of Shandong Province/ ; },
abstract = {Pathogenic amyloid-β (Aβ) accumulation defines Alzheimer's disease (AD), directly inflicting neuronal damage and driving chronic neuroinflammation. While both central microglia and peripheral macrophages are critical for Aβ clearance, their functional impairment in AD inexorably leads to escalating Aβ burden and disease progression. We here report an in situ engineered synthetic Aβ disaggregator (SAD) delivered to macrophages via neuroprotective DHA-based lipid nanoparticles (DLNPs). This platform transcends current therapeutic limitations by not only potently dismantling neurotoxic Aβ aggregates but also by fundamentally reprogramming peripheral macrophages to enhance Aβ clearance. Specifically, our results demonstrate that DLNPs effectively reprogram peripheral macrophages to produce and secrete cerebral-penetrating SAD both in vitro and in vivo. The SAD can promote cerebral Aβ disaggregation, thereby inhibiting neuroinflammatory pathology progression. Moreover, the DLNPs efficiently reprogram the peripheral macrophages to enhance phagocytosis, further facilitating drainage of Aβ and reducing cerebral Aβ accumulation in mouse models. Collectively, these findings uncover a dual-action mechanism of SAD through the synergistic interplay of direct Aβ disaggregation and enhanced macrophage-mediated clearance. In sum, our findings establish that the central-peripheral targeting therapeutic strategy significantly reversed AD pathology, highlighting the therapeutic potential of mRNA-based in situ fusion protein in AD treatment.},
}

@article {pmid41510365,
year = {2026},
author = {Wang, Y and Alexander, GC and Mehta, HB},
title = {Treatment of type 2 diabetes among medicare beneficiaries with and without alzheimer's disease: A retrospective cohort study.},
journal = {Journal of diabetes and metabolic disorders},
volume = {25},
number = {1},
pages = {25},
pmid = {41510365},
issn = {2251-6581},
abstract = {PURPOSE: While Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) commonly co-occur in older adults, little is known regarding whether and how the treatment of T2DM varies by AD status. This study aimed to compare and contrast T2DM treatment among individuals with and without AD.

METHODS: We conducted a retrospective cohort study using 20% Medicare Fee-for-Service claims data from 2016 to 2020. The primary outcome was initiation of any antidiabetic medication within one year of T2DM diagnosis, and we also examined initiation patterns across specific drug classes. We used multivariable logistic regression to estimate adjusted odds ratios for the association between AD and treatment initiation.

RESULTS: Among 388,359 beneficiaries newly diagnosed with T2DM, 9,584 had AD. Within one year, overall treatment initiation was lower for individuals with AD compared to those without. At initiation, individuals with AD were more likely to receive insulin and less likely to receive metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists. In adjusted models, AD was associated with lower odds of antidiabetic treatment initiation, and among those initiating treatment, lower odds of initiating newer agents such as GLP-1 receptor agonists and SGLT2 inhibitors.

CONCLUSION: Beneficiaries with AD were less likely to initiate antidiabetic therapy, particularly newer agents. Future work could explore the basis for these differences.},
}

@article {pmid41510304,
year = {2025},
author = {Wang, Y and Zhou, M and Tang, Z and Xiong, C and Asken, B and Yang, B and Su, J and Zhou, X and Song, Q},
title = {CauReL: Dynamic Counterfactual Learning for Precision Drug Repurposing in Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8206648/v1},
pmid = {41510304},
issn = {2693-5015},
abstract = {Alzheimer's disease has few effective therapies, and decades of amyloid- and tau-focused trials have delivered only modest benefit with substantial toxicity. Drug repurposing using real-world data offers a faster and lower-risk route to new treatments, yet current approaches typically average effects across populations, model disease onset and progression separately, and provide little insight into which patients are most likely to benefit. We present CauReL, a dynamic counterfactual representation learning framework that enables transparent, patient specific estimation of treatment effects from large-scale electronic health records for precision drug repurposing in AD. CauReL first learns balanced latent representations of treated and untreated patients using Integral Probability Metric regularization, then jointly predicts two clinically linked outcomes, incident AD and time from mild cognitive impairment (MCI) to AD, to generate paired counterfactual outcomes for every individual. A counterfactual explanation module quantifies how clinical features shape benefit at the patient level, and uplift trees transform complex heterogeneity into simple, rule-based subgroups suitable for trial enrichment and clinical decision support.Using independent cohorts from OneFlorida + and All of Us, we screened outpatient prescriptions with at least 20 percent exposure among 28,605 individuals with mild cognitive impairment, of whom 4,990 progressed to Alzheimer's disease. CauReL substantially improved covariate balance and distributional overlap across drug cohorts and achieved strong predictive accuracy for both incidence (AUC greater than 0.90) and progression timing (C index 0.81 to 0.84; Spearman 0.80 to 0.86). Twenty drugs showed consistent protective associations, with four emerging as highly reproducible across both networks, the metabolic agents liraglutide and empagliflozin and the neuroactive agents entacapone and amantadine. These drugs were associated with meaningful absolute risk reductions and clinically significant delays in progression from mild cognitive impairment to Alzheimer's disease. Metabolic drugs produced the strongest benefits in individuals with diabetes, obesity, or cardiovascular disease, whereas neuroactive drugs provided broadly consistent protection across most subgroups.CauReL is available as an open source Python package with a companion web server for direct application to new cohorts or disease settings (https://caurel.site/). This work delivers a scalable and interpretable framework for prioritizing repurposable drugs and designing targeted clinical trials for the patients most likely to benefit.},
}

@article {pmid41510223,
year = {2025},
author = {Jiang, L and Tucker, A and Sepehri, C and Patel, D and Wang, Q and Yuan, S and Sherman, E and Chen, Y and Beh, J and Downey, A and Goldberg, D and Gniadzik, W and Ma, X},
title = {Inhibition of N6-Methyladenosine Accumulation by Targeting METTL3 Mitigates Tau Pathology and Cognitive Decline in Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8379573/v1},
pmid = {41510223},
issn = {2693-5015},
abstract = {Dysregulation of N6-methyladenosine (m6A) modification of RNA has emerged as a novel feature of Alzheimer's disease (AD). Here, we investigate the relationship between m6A modification and AD pathology, and the therapeutic potential of modulating excessive m6A via its "writer" methyltransferase METTL3 in a humanized P301S tau transgenic mouse model of AD (PS19). We observed significantly elevated m6A levels in human post-mortem AD frontal cortex tissue compared to healthy controls, which positively correlated with hyperphosphorylated tau and amyloid-β (Aβ) deposition. These effects were recapitulated in the PS19 tau mice model of AD. Importantly, treatment of PS19 mice with the METTL3 inhibitor STM2457 reduced excessive m6A, alleviated tau pathology, and attenuated neurodegeneration. Behavioral assessments further demonstrated that STM2457-treated PS19 mice exhibited significantly improved learning and memory relative to untreated PS19 mice. Our results identify m6A as a critical contributor to AD pathogenesis and demonstrate that pharmacological inhibition of METTL3 represents a promising therapeutic strategy to improve cognition in AD.},
}

@article {pmid41509358,
year = {2026},
author = {Jati, S and Kal, S and Munoz-Mayorga, D and Tang, K and Sahoo, D and Chen, X and Mahata, SK},
title = {Catestatin ameliorates tauopathy and amyloidogenesis via adrenergic inhibition.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.04.697519},
pmid = {41509358},
issn = {2692-8205},
abstract = {Neurodegenerative disorders like Alzheimer's disease (AD), Corticobasal Degeneration (CBD), and Progressive Supranuclear Palsy (PSP) are characterized by Tau aggregation, synaptic dysfunction, neuroinflammation, and progressive cognitive decline. Although metabolic dysregulation and neuropeptide imbalance have been linked to these disorders, the functional consequences of such imbalance and its potential for therapeutic reversal remain poorly understood. Our previous work identified chromogranin A (CgA), which encodes a pro-hormone for several metabolic peptides, as a key regulator of Tau pathology. Here, we investigate Catestatin (CST), a CgA-derived peptide that is a potent inhibitor of catecholamine release and has been shown to increase insulin sensitivity and lower peripheral blood pressure. We report significant reductions in CST levels in the hippocampus and cortex of AD brains, as well as in the frontal cortex of CBD and the basal ganglia of PSP. Supplementing CST in cortical neuronal cultures and organotypic slice cultures (OTSC) decreased Tau phosphorylation and aggregation. In vivo , CST administration in PS19 Tauopathy mice reduced pathological Tau species, attenuated gliosis, and improved cognitive function. CST treatment also lowered amyloid plaque burden and neuroinflammation in 5xFAD mice. Mechanistically, CST decreased epinephrine (EPI) levels in both PS19 and 5xFAD mice and suppressed downstream protein kinase A (PKA) hyperactivation in PS19 and OTSC. These findings reveal a previously unrecognized neuropeptidergic mechanism linking CST deficiency to elevated adrenergic receptor (ADR)-EPI-PKA stress signaling and Tauopathy-driven neurodegeneration, suggesting CST replacement as a promising therapeutic approach.},
}

@article {pmid41509252,
year = {2026},
author = {Jesudason, CD and Rangel-Barajas, C and Beach, CJ and Beck, DE and Caballero-Floran, IH and Clayton, WB and Da Silva, L and David, JC and Doolen, S and Faulkner, AN and Hamdani, AK and Huhe, H and Huynh, K and Imhoff, RD and Javens-Wolfe, J and Mason, ER and Moussaif, M and Singhal, K and Soni, DM and van Buuren-Milne, M and Williams, SP and Angus, SP and Chu, S and Dage, JL and Hipskind, PA and Johnson, TS and Kaddurah-Daouk, R and Lamb, BT and Meikle, PJ and Mesecar, AD and Palkowitz, AD and Quinney, SK and Sukoff Rizzo, SJ and Oblak, AL and Richardson, TI},
title = {Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer's Disease Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.31.697127},
pmid = {41509252},
issn = {2692-8205},
abstract = {Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1), encoded by the gene INPP5D, is a lipid phosphatase that negatively regulates immune receptor signaling in hematopoietic cells and microglia. Here, we describe a pyridyl-pyrazole-piperidine scaffold and the lead compound 3-((2-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine (32), which demonstrates SHIP1 target engagement, brain exposure, and evidence of a central pharmacodynamic response in vivo . Structure-activity relationship studies, guided by biochemical and cellular assays using multiple human and murine protein constructs and cells, identified SHIP1-active ligands. A thermal shift assay using full-length SHIP1 was used to assess compounds for cellular target engagement, while studies in IL-4 conditioned THP-1 cells was used to demonstrate changes in downstream AKT signaling. Targeted lipidomics revealed changes in the overall phosphoinositide pool consistent with SHIP1 target engagement and reduction of phospho-AKT levels. In a protein-lipid overlay assay, compound 32 induced changes in the relative association of SHIP1 with multiple phosphatidylinositols on a membrane surface. In high-content cellular imaging assays, compound 32 enhanced the uptake of myelin/membrane debris and fibrillar amyloid by primary murine microglia, phenocopying a genetic model with reduced SHIP1 expression. Finally, oral administration of compound 32 resulted in brain exposure sufficient to alter gene expression and reduce IL-1β levels as pharmacodynamic markers of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimer's disease. Collectively, these results define a scaffold with SHIP1 target engagement, CNS exposure, and in vivo activity, providing a foundation for the optimization of brain-penetrant SHIP1 ligands suitable for further mechanistic studies and therapeutic development for the treatment of Alzheimer's disease.},
}

@article {pmid41509242,
year = {2025},
author = {Kumari, R and Bowen, C and Srivastava, U and Brandelli, AD and Kumar, P and Kour, D and Malepati, S and Jang, WE and Bromwich, M and Zeng, H and Sing, A and Sloan, SA and Wulff, H and Rangaraju, S},
title = {Kv1.3 inhibition alleviates neuropathology via neuroinflammatory and resilience pathways in a mouse model of Aβ pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.25.696456},
pmid = {41509242},
issn = {2692-8205},
abstract = {Inhibition of voltage-gated potassium channel Kv1.3 is a therapeutic strategy to curb microglia-mediated neuroinflammation in neurodegeneration, although the cellular and signaling mechanisms of disease-modification by Kv1.3 blockers are unclear. In this study, we delineate protective mechanisms of Kv1.3 blockade in a mouse model of Alzheimer's disease (AD) pathology using comprehensive transcriptomics and proteomics profiling of brain, corresponding with neuropathological effects of two translationally relevant Kv1.3 blockers, namely small molecule PAP-1 and peptide ShK-223. Following 3 months of treatment, both molecules reduced Ab plaque burden. Single nuclear RNA seq (snRNA seq) of brain nuclei showed that PAP-1 disproportionately impacted oligodendrocytes and microglia and increased crosstalk between neurons and astrocytes with endothelial cells. In contrast, ShK-223 had pronounced effects on glutamatergic neurons and astrocytes. Both blockers increased expression of myelination genes in oligodendrocytes and synaptic genes in neurons. Neuroprotective effects of PAP-1 were further confirmed by bulk brain transcriptomics and proteomics whereby PAP-1 increased levels of synaptic, cognitive resilience and mitochondrial proteins, while decreasing glial and immune pathways including STAT1/3 phosphorylation. Using proximity labeling and co-immunoprecipitation, we found that Kv1.3 interacts with STAT1/3 in microglia. Using microglial cell lines and primary microglia, we discovered a preferential functional coupling between Kv1.3 and type 2 but not type 1 IFN signaling. Brain-level disease modification by Kv1.3 blockade was reflected in the cerebrospinal fluid (CSF) via reduced levels of neurofilament-light (NEFL) and resilience protein RPH3A, both of which are increased in human AD CSF. Together, this study demonstrates functional links between Kv1.3 channels and type 2 IFN signaling and reveals distinct cellular effects of Kv1.3 blockers in AD pathology that correspond with reduced neuropathology and neuroinflammation, augmentation of resilience and neuro-vascular pathways, along with biomarkers of therapeutic effect.},
}

@article {pmid41508224,
year = {2025},
author = {Ma, YJ and Deng, SX and Liao, ZH and Gao, MH and Ding, HX and Xu, ZQ and Lu, YT and Yang, C and Wang, Q},
title = {[Treatment of Alzheimer's disease from gut-brain interactions based on theory of "spleen deficiency leading to obstruction of nine orifices"].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {19},
pages = {5330-5339},
doi = {10.19540/j.cnki.cjcmm.20250618.501},
pmid = {41508224},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy/physiopathology/metabolism ; Humans ; *Brain/physiopathology/drug effects/metabolism ; *Spleen/physiopathology/drug effects ; Animals ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use ; Gastrointestinal Microbiome ; },
abstract = {Alzheimer's disease(AD) is the most common form of dementia. The decline in sensory function is associated with pathological damage in specific brain regions during the early stages of AD. Such decline often precedes cognitive impairment, worsens as the pathology progresses, and constitutes a high-risk factor for the onset of AD. According to traditional Chinese medicine(TCM), all orifices are connected to the brain, and the brain governs all orifices. The mind originates from and depends on both the brain and orifices, with their physiological and pathological states being closely interconnected. In AD, dysfunction of the sensory orifices is closely linked to the later-stage manifestations of impaired mental clarity and consciousness. The theory that "spleen deficiency leading to obstruction of nine orifices" emphasizes that insufficiency of the spleen and stomach is the root cause of orifice dysfunction. Both internal and external pathogenic factors in AD can damage the spleen and stomach, leading to the abnormal movement of turbid substances generated by these organs, which may transform into turbid toxins. This, in turn, gradually impairs the orifices, brain, and mind, thereby exacerbating the progression of AD. The digestive, absorptive, and transport functions of the spleen and stomach are similar to those of the gut microbiota. Spleen deficiency is a core pathological factor in diseases associated with gut microbiota dysbiosis. Such dysbiosis can lead to dysfunction in the neural, metabolic, and immune pathways involved in gut-brain interactions, constituting the biological basis for the TCM concept that "spleen deficiency leading to obstruction of nine orifices". Under the guidance of this theory, employing spleen-strengthening and cognition-enhancing drugs alongside aromatic orifice-opening drugs to support spleen function, and using ingredients that promote dampness elimination, lubrication, and blood stasis resolution to dispel pathogenic factors from the orifices, can help restore the structural balance of the gut microbiota, regulate related metabolic and immune dysfunctions, and ultimately delay the progression of AD. This article explores the etiology, pathogenesis, and therapeutic strategies of AD based on the theory of "spleen deficiency leading to obstruction of nine orifices", and interprets its biological significance from the perspective of gut-brain interactions, aiming to provide new insights for the prevention and treatment of AD.},
}

*Alzheimer Disease/drug therapy/physiopathology/metabolism
Humans
*Brain/physiopathology/drug effects/metabolism
*Spleen/physiopathology/drug effects
Animals
Medicine, Chinese Traditional
Drugs, Chinese Herbal/therapeutic use
Gastrointestinal Microbiome

@article {pmid41508200,
year = {2025},
author = {Zhang, YX and Wang, J and Chen, QQ and Zhang, JL and Wang, Q and Long, YL and Zhou, SJ and Gong, ZP and Zheng, L and Huang, Y and Li, YT},
title = {[Study on quality markers of Pleione yunnanensis for "same treatment for different diseases" in liver inflammation and Alzheimer's disease based on UHPLC fingerprint and network pharmacology].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {20},
pages = {5684-5696},
doi = {10.19540/j.cnki.cjcmm.20250710.202},
pmid = {41508200},
issn = {1001-5302},
mesh = {Network Pharmacology ; *Drugs, Chinese Herbal/chemistry/therapeutic use ; *Alzheimer Disease/drug therapy/genetics/metabolism ; Chromatography, High Pressure Liquid/methods ; Humans ; Molecular Docking Simulation ; Biomarkers/analysis ; Quality Control ; },
abstract = {This study aims to screen quality markers(Q-markers) of Pleione yunnanensis for the treatment of liver inflammation and Alzheimer's disease(AD) based on the concept of "same treatment for different diseases" using ultra-high-performance liquid chromatography(UHPLC) fingerprinting combined with network pharmacology and molecular docking, and to perform quantitative analysis of the identified Q-markers. The UHPLC fingerprints of 15 batches of P. yunnanensis were established and subjected to similarity evaluation, cluster analysis(CA), principal component analysis(PCA), and orthogonal partial least squares discriminant analysis(OPLS-DA) to identify characteristic components responsible for quality variations. Network pharmacology and molecular docking were employed to explore the potential active components, related targets, and signaling pathways underlying the "same treatment for different diseases" mechanism for liver inflammation and AD. Based on the criteria of effectiveness, specificity, and measurability, Q-markers of P. yunnanensis were identified and quantified. Ten common peaks were identified in the UHPLC fingerprints of 15 batches, with eight components identified. Similarity scores ranged from 0.774 to 0.987. Chemical pattern recognition analysis identified that shancigusin H, militarine, and gymnoside Ⅴ were the major characteristic components contributing to quality differences among batches. RESULTS:: of network pharmacology and molecular docking revealed that dactylorhin A and militarine were the key active components exerting anti-inflammatory and neuroprotective effects. These components acted on 13 core targets, including SRC, CASP3, and CTNNB1, and regulated signaling pathways such as the PI3K-Akt signaling pathway and arachidonic acid metabolism. Based on the effectiveness, specificity, and measurability of Q-marker, dactylorhin A and militarine were selected as the Q-markers of P. yunnanensis. Quantitative analysis demonstrated that the content of dactylorhin A ranged from 0.527% to 2.21%, and militarine ranged from 0.731% to 2.58% across the 15 batches. The UHPLC fingerprint method and Q-marker-based quantification approach are robust and reliable, providing experimental evidence for quality control and standardization of P. yunnanensis.},
}

Network Pharmacology
*Drugs, Chinese Herbal/chemistry/therapeutic use
*Alzheimer Disease/drug therapy/genetics/metabolism
Chromatography, High Pressure Liquid/methods
Humans
Molecular Docking Simulation
Biomarkers/analysis
Quality Control

@article {pmid41508178,
year = {2025},
author = {Hou, WX and Liu, YX and Miao, JR and Zhu, ZK and Yin, Y and Liu, JL and Zhao, DY},
title = {[Mechanism of Liuwei Dihuang Pills in enhancing GPNMB expression to regulate FcγRⅡB/c-Src pathway for prevention and treatment of Alzheimer's disease].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {21},
pages = {6062-6071},
doi = {10.19540/j.cnki.cjcmm.20250805.401},
pmid = {41508178},
issn = {1001-5302},
mesh = {Animals ; *Drugs, Chinese Herbal/administration & dosage ; *Alzheimer Disease/drug therapy/genetics/metabolism/prevention & control ; Male ; Mice ; *Membrane Glycoproteins/genetics/metabolism ; Humans ; Signal Transduction/drug effects ; *src-Family Kinases/metabolism/genetics ; Hippocampus/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Memory/drug effects ; Eye Proteins ; },
abstract = {This study investigated the effect of Liuwei Dihuang Pills on the Fcγ receptor Ⅱ-b(FcγRⅡB)/c-Src tyrosine kinase(c-Src) pathway in senescence-accelerated mouse prone 8(SAMP8) by regulating the expression of the glycoprotein non-metastatic melanoma protein B(GPNMB) and explored the mechanism of the kidney-tonifying and essence-strengthening therapy in the treatment of Alzheimer's disease.(1) For the effects of Liuwei Dihuang Pills on the learning and memory ability, hippocampal β-amyloid protein(Aβ), GPNMB, and autophagy function in SAMP8 mice, eight seven-month-old male senescence-accelerated mouse resistant 1(SAMR1) mice were used as a control group, and 16 male SAMP8 mice of the same age were randomly divided into a model group and a Liuwei Dihuang Pills group. The Liuwei Dihuang Pills group was given 2.36 g·kg~(-1) concentrated Liuwei Dihuang Pills solution by gavage, while the control group and the model group were given the same volume of normal saline twice a day for four consecutive weeks. The learning and memory ability of mice in each group was detected by the Morris water maze experiment; the expression level of Aβ in the hippocampus of mice were detected by enzyme-linked immunosorbent assay(ELISA) and immunohistochemistry; the expression of GPNMB in the hippocampus of mice was detected by immunofluorescence and Western blot; the expression level of ubiquitin-binding protein p62 and microtubule-associated protein light chain 3(LC3) Ⅱ/LC3Ⅰ in the hippocampus of mice was measured by Western blot.(2) For the regulatory effect of GPNMB on the FcγRⅡB/c-Src pathway, eight seven-month-old male SAMR1 mice were used as a control group, and 24 male SAMP8 mice of the same age were randomly divided into a model group, an LV-Vector group, and an LV-GPNMB~(OE) group. The bilateral hippocampus of the LV-Vector group and LV-GPNMB~(OE) group was injected with LV-Vector and LV-GPNMB~(OE) of 2 μL/each side, respectively. Western blot was used to detect the expression level of p62, LC3Ⅱ/LC3Ⅰ, FcγRⅡB, Src homology 2 protein tyrosine phosphatase 1(SHP-1), and c-Src proteins in the hippocampus of mice.(3) For the effect of Liuwei Dihuang Pills in regulating the FcγRⅡB/c-Src pathway by increasing the GPNMB expression, 32 seven-month-old male SAMP8 mice were randomly divided into a model group, a Liuwei Dihuang Pills group, a Liuwei Dihuang Pills + LV-NC group, and a Liuwei Dihuang Pills + LV-shGPNMB group. The bilateral hippocampus of the Liuwei Dihuang Pills + LV-NC group and Liuwei Dihuang Pills + LV-shGPNMB group was injected with LV-NC and LV-shGPNMB, respectively, before the drug treatment. Western blot was used to detect the expression level of p62, LC3Ⅱ/LC3Ⅰ, FcγRⅡB, SHP-1, and c-Src proteins in the hippocampus of mice. The results showed that(1) compared with those of the control group, the escape latency of the model group was significantly increased, and the time spent in the target quadrant and the effective area was significantly decreased. The expression level of Aβ, GPNMB, and p62 in the hippocampus was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. Compared with those of the model group, the escape latency of the Liuwei Dihuang Pills group was significantly shortened, and the time spent in the target quadrant and the effective area was significantly increased. The level of Aβ was significantly decreased, and the expression level of GPNMB was significantly increased. The expression level of p62 was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased.(2) Compared with those of the control group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src proteins in the hippocampus of the model group was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. Compared with those of the model group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the LV-GPNMB~(OE) group was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased.(3) Compared with those of the model group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the Liuwei Dihuang Pills group was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased. Compared with those of the Liuwei Dihuang Pills group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the Liuwei Dihuang Pills + LV-shGPNMB group was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. These results indicate that Liuwei Dihuang Pills can inhibit the FcγRⅡB/c-Src pathway by up-regulating the GPNMB expression, thereby increasing autophagy levels, enhancing neuroprotective ability, and alleviating Alzheimer's disease.},
}

Animals
*Drugs, Chinese Herbal/administration & dosage
*Alzheimer Disease/drug therapy/genetics/metabolism/prevention & control
Male
Mice
*Membrane Glycoproteins/genetics/metabolism
Humans
Signal Transduction/drug effects
*src-Family Kinases/metabolism/genetics
Hippocampus/drug effects/metabolism
Amyloid beta-Peptides/metabolism
Memory/drug effects
Eye Proteins

@article {pmid41508060,
year = {2025},
author = {Sun, CX and Han, XY and Xiao, YT and Liu, YX and Ye, TY},
title = {[Research progress on prevention and treatment of Alzheimer's disease with Danggui Shaoyao San].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {22},
pages = {6215-6226},
doi = {10.19540/j.cnki.cjcmm.20250626.601},
pmid = {41508060},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy/prevention & control/metabolism ; *Drugs, Chinese Herbal/therapeutic use/administration & dosage ; Humans ; Animals ; },
abstract = {Alzheimer's disease is a neurodegenerative disorder associated with aging. In traditional Chinese medicine(TCM), it is classified as a syndrome of root deficiency and branch excess. Danggui Shaoyao San, a classic formula traditionally used to treat gynecological disorders, has the effects of promoting blood circulation, removing blood stasis, opening orifices, awakening the mind, strengthening the spleen, resolving phlegm, and tonifying Qi to nourish the spirit. Modern clinical studies have found that Danggui Shaoyao San can slow the progression of Alzheimer's disease and has great potential for clinical application. Recent studies indicate that Danggui Shaoyao San treats Alzheimer's disease through multi-target and multi-level mechanisms. These include clearing amyloid β(Aβ) plaques and abnormally phosphorylated tau protein, maintaining brain-gut homeostasis, reducing oxidative stress, and regulating autophagy. Its key components, paeoniflorin and ferulic acid, have also been reported to exert antioxidant, anti-inflammatory, and anti-apoptotic effects, eliminate pathological products, and regulate the cholinergic system in the brain. This paper traces the classic formula of Danggui Shaoyao San, conducts a theoretical integration of ancient and modern medical systems, and systematically summarizes and analyzes the research related to the treatment of Alzheimer's disease using Danggui Shaoyao San and its key components. It aims to provide a valuable reference for further research and modern application of Danggui Shaoyao San in the treatment of Alzheimer's disease.},
}

*Alzheimer Disease/drug therapy/prevention & control/metabolism
*Drugs, Chinese Herbal/therapeutic use/administration & dosage
Humans
Animals

@article {pmid41507065,
year = {2026},
author = {De Rui, M and Salerno Trapella, G and Ceolin, C and Ceccato, F and Antonelli, G and Ravelli, A and Andreuzza, R and Conti, E and Sarlo, M and Coin, A and Zanforlini, BM and Bertocco, A and Curreri, C and Tizianel, I and Mapelli, D and Sergi, G and Devita, M},
title = {Effect of cognitive training on cortisol levels in patients with neurocognitive disorders.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbaf243},
pmid = {41507065},
issn = {1758-5368},
abstract = {OBJECTIVES: Elevated cortisol levels are linked to a greater risk and faster progression of neurocognitive disorders (NCDs). While interventions such as exercise and mindfulness have shown benefits in reducing cortisol, the impact of cognitive training (CT) on cortisol regulation remains unexplored. This study investigated whether CT affects cortisol levels and secretion patterns in individuals with minor or major NCD and compared its effects with those of pharmacological treatment.

METHODS: Sixty-two older adults with NCD and 43 healthy controls were recruited from the University Hospital of Padua in Italy. Among patients with NCD, 34 underwent CT (CT-NCD group), and 28 received pharmacological treatment (PH-NCD group). Salivary cortisol was measured at six points during the day, at baseline, and at 3 months (T1) and 6 months (T2) post-intervention.

RESULTS: Compared with pharmacological treatment (PH), CT showed a larger percentage decrease of daily cortisol exposure (AUC) from baseline; however, the between-group difference did not remain statistically significant after covariate adjustment, and the only robust time-point effect was in the afternoon (F(1,47)=5.13; p = 0.028). Morning values decreased within groups, but between-group differences in the CAR were not significant; at bedtime, CT showed only a trend towards lower cortisol than PH (p = 0.071). Median morning values changed from 7.75 to 6.20 in CT and from 5.80 to 5.15 in PH.

DISCUSSION: CT may help lower cortisol levels and enhance cognitive function in NCD patients, suggesting its potential as a nonpharmacological tool to modulate hypothalamic-pituitary-adrenal axis activity. Larger randomized studies are needed to confirm and extend these findings.},
}

@article {pmid41506855,
year = {2025},
author = {Lizama, BN and Caro, VD and Cho, E and Caldwell, J and Pandey, K and Duong, DM and Seyfried, NT and Grundman, M and Caggiano, AO and Teunissen, CE and Hamby, ME},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107075},
doi = {10.1002/alz70856_107075},
pmid = {41506855},
issn = {1552-5279},
mesh = {Humans ; Biomarkers/blood ; Double-Blind Method ; Male ; *Alzheimer Disease/drug therapy/blood ; Female ; Aged ; Proteomics ; Cognitive Dysfunction/drug therapy/blood ; Receptors, sigma ; },
abstract = {BACKGROUND: Participants with Alzheimer's disease (AD) treated with sigma-2 receptor (S2R) modulator zervimesine (CT1812) exhibited 39% slowing of cognitive decline (ADAS-Cog11) compared to placebo in the mITT cohort of the SHINE trial (NCT03507790, COG0201). The pre-specified below-median pTau217 subgroup showed 95% slowing with zervimesine, and significant decrease in plasma-GFAP, a neuroinflammation biomarker, compared to placebo (-28.35 ± 11.687 SEM, p = 0.0186). Given favorable outcomes with zervimesine treatment in the below-median pTau217 subgroup, a plasma proteomic biomarker sub-study assessing correlation of plasma proteins with plasma-GFAP was performed to elucidate protective mechanisms of zervimesine.

METHOD: SHINE was a Phase 2 randomized, double-blind, placebo-controlled study. Participants (N = 152) received a daily oral dose of zervimesine (100 or 300 mg) or placebo for 6-months (end-of-study, EOS). A proteomics sub-study of 60 participants was performed using tandem-mass tag mass spectrometry (TMT-MS) of plasma collected at baseline and EOS, with downstream analyses from treatment-compliant participants (mITT N = 57). For subgroup analysis, plasma from participants with median baseline plasma p-Tau217 concentration (ALZpath, SIMOA) <1pg/mL was analyzed (N = 24). Change from baseline (CFB) was calculated, and Pearson correlation analysis was performed with plasma-GFAP (assessed via SIMOA) and protein levels, assessed via proteomics, from either 1) placebo and drug-treated (all-participants analysis) or 2) drug-only treated participants (drug-only analysis). Pathway analysis was performed on correlated proteins (p≤0.05).

RESULT: TMT-MS of plasma detected 1674 proteins, from which 45 were correlated to GFAP in the all-participants analysis and 284 in drug-only analysis (p≤0.05). Thirteen proteins were overlapping between the all-participants and drug-only analyses, including inflammation-related proteins ALOX12 and CTSG, and lysosomal protein LAMP1. To further home in on pharmacodynamic biomarkers of zervimesine, the 13 overlapping correlates were excluded, allowing for 271 proteins specifically correlated with drug treatment to be identified (p≤0.05). These proteins were enriched in vesicle-mediated transport and inflammation-related pathways (FDR≤0.05).

CONCLUSION: The correlates identified may represent an inflammatory signature tied to the decreased neuroinflammation (plasma-GFAP) with zervimesine in AD patients observed in the pTau217 biomarker-defined subgroup (below the median). Results support a role for zervimesine in decreasing neuroinflammation and the continued clinical development of zervimesine for AD.},
}

Humans
Biomarkers/blood
Double-Blind Method
Male
*Alzheimer Disease/drug therapy/blood
Female
Aged
Proteomics
Cognitive Dysfunction/drug therapy/blood
Receptors, sigma

@article {pmid41506734,
year = {2026},
author = {, and , },
title = {[Guidelines for the management of chronic insomnia comorbid with common neuropsychiatric disorders in adults (2025 edition)].},
journal = {Zhonghua nei ke za zhi},
volume = {65},
number = {1},
pages = {18-44},
doi = {10.3760/cma.j.cn112138-20250911-00539},
pmid = {41506734},
issn = {0578-1426},
support = {2021YFC2501400//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Sleep Initiation and Maintenance Disorders/therapy/epidemiology/complications ; *Mental Disorders/therapy/complications/epidemiology ; Comorbidity ; Adult ; Parkinson Disease ; },
abstract = {Chronic insomnia frequently co-occurs with common neuropsychiatric disorders, including migraine, stroke, Alzheimer's disease, Parkinson's disease, epilepsy, generalized anxiety disorder, depressive disorder, body distress disorder, post-traumatic stress disorder, and disorders due to use of alcohol. The prevalence of these neuropsychiatric disorders is hiher among patients with chronic insomnia than in the general population, and the conditions mutually exacerbate each other. Comorbidities not only exacerbate the severity and increases the relapse risk of each condition but also lead to a poorer prognosis, more severe impairment of social functioning, a higher all-cause mortality risk, and greater treatment challenges. Therefore, the Sleep Disorders Group, Chinese Society of Neurology and Sleep Medicine Group,China Neurologist Association have convened experts in relevant fields, based on current medical evidence, to establish guideline for the management of Chinese adults with chronic insomnia comorbid with the aforementioned 10 categories of common neuropsychiatric disorders. The aim is to standardize clinical practice and improve treatment effectiveness and cure rates.},
}

Humans
*Sleep Initiation and Maintenance Disorders/therapy/epidemiology/complications
*Mental Disorders/therapy/complications/epidemiology
Comorbidity
Adult
Parkinson Disease

@article {pmid41506719,
year = {2025},
author = {Song, Z and Huang, X and Liu, J and Chen, J and Johnson, TS and Zhang, J and Huang, K},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107088},
doi = {10.1002/alz70856_107088},
pmid = {41506719},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnosis/classification/metabolism ; *Biomarkers ; Male ; Female ; Aged ; Proteomics ; Algorithms ; Disease Progression ; DNA Methylation ; },
abstract = {BACKGROUND: Distinguishing Alzheimer's Disease (AD) subtypes can improve disease diagnosis, treatment, and management. This study uses Graph Attention Networks (GAT) and a cross-attention algorithm to integrate multi-omics data and characterize distinct AD subtypes.

METHOD: Three omics datasets, including transcriptomics, proteomics, DNA methylation, and clinical information from 156 Religious Orders Study and Rush Memory and Aging Project (ROSMAP) patients and controls, were integrated using a Graph Attention Network (GAT) and a cross-attention mechanism. GAT encoders generated embeddings for each omics graph, which were integrated via pairwise cross-attention and combined with clinical data through projection layers. A multi-task loss combining cross-entropy and reconstruction losses was used for training, yielding integrated embeddings representing the molecular complexity of AD (Figure 1). Pseudotime for all patients was calculated using the Partition-based Graph Abstraction (PAGA) method to compare disease progression trajectories across subtypes identified by KMeans. Differentially expressed genes (DEGs) and clinical differences between AD-enriched clusters were evaluated to characterize AD subtypes, and gene set enrichment analysis identified molecular functions, biological processes, and cellular components enriched among DEGs.

RESULT: Four clusters were identified: two enriched in controls and two in AD (Figure 2). This study focuses on comparing the two AD subtypes. Pseudotime analysis showed significant trajectory differences among all clusters, particularly between the AD subtypes (adjusted p < 0.01), indicating distinct disease trajectories. Demographic factors age, sex, and APOE status, showed no significant differences between the two subtypes. Cognitive status differed significantly, with one AD subtype including more patients with mild cognitive impairment (MCI). Additionally, 75 DEGs between the two subtypes were identified (FDR < 0.05 and logFC > 0.7), along with 126 significant molecular processes, 3 biological functions, and 38 cell components were identified, with adjusted p-values < 0.1 (Figure 3).

CONCLUSION: The pipeline integrated multimodal omics data and successfully identified two AD subtypes with distinct disease progression. The 75 DEGs are enriched cellular response to copper ions, hormone activity, and mitochondrial respiratory chain complex I and clathrin-sculpted vesicles, which we believe play important roles in AD pathogenesis and differentiate the two subtypes.},
}

Humans
*Alzheimer Disease/genetics/diagnosis/classification/metabolism
*Biomarkers
Male
Female
Aged
Proteomics
Algorithms
Disease Progression
DNA Methylation

@article {pmid41506617,
year = {2025},
author = {Verbel, D and Niu, H and Reyderman, L and Irizarry, MC and Sachdev, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107102},
doi = {10.1002/alz70856_107102},
pmid = {41506617},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *alpha-Synuclein/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Male ; Female ; Aged ; Disease Progression ; *Cognitive Dysfunction/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Lewy Body Disease/cerebrospinal fluid ; Positron-Emission Tomography ; },
abstract = {BACKGROUND: Existing copathologies, such as Lewy body (LB) disease, can introduce heterogeneity to AD pathogenesis and presentation of symptoms and likely influence disease progression. A seed amplification assay (SAA) that detects aggregated, misfolded α-synuclein (α-syn) can detect LB. Incorporation of SAA can characterize disease heterogeneity in AD and potentially predict disease progression.

METHODS: A validated SAA was used to characterize α-syn SAA status (Amprion Clinical Laboratory) in baseline CSF samples collected from a Phase 3 program for elenbecestat in subjects with MCI or mild dementia due to AD (NCT02956486). Samples were selected by PET visual read status. The sample set was enriched using subjects considered to be progressors or non-progressors based on change in cognition (CDR-SB) at 18 months, before assessment of SAA status. Results of α-syn status were reported as Detected, Not Detected, or Indeterminate. The proportion of samples defined as Detected and Not Detected were summarized by amyloid status. Cognition, at baseline and longitudinally, was summarized by amyloid and α-syn status. Available baseline A/T/N biomarkers were also summarized and compared.

RESULTS: Among the 201 samples that were included in the analyses, 15% of amyloid+ and 8% of amyloid- MCI/early AD subjects were determined to be SAA+ and hence determined to have LB copathology. In comparison, in ADNI, 17% of cognitively unimpaired (CU) subjects; 20% of MCI subjects and 39% of AD subjects had synuclein copathology (Tosun et al Alzheimer's Dement. 2024). In BioFinder2, synuclein copathology was detected in 8%, 17% and 23% of CU, MCI, and AD subjects, respectively (Palmqvist et al and Quadalti et al Nature Medicine 2023). The longitudinal trajectory of amyloid positive subjects with α-syn copathology seemed to have faster cognitive decline in natural history studies. In the Phase 3 samples, the longitudinal cognitive trajectory showed trend towards faster decline over 18 months in the amyloid+ subjects with α-syn copathology; however, this did not appear significant.

CONCLUSION: LB, a common copathology of AD, may be a source of heterogeneity. Incorporation of SAA, a specific biomarker of LB-pathology, can help account for disease heterogeneity and potentially improve assessment of treatment response in amyloid and synuclein status confirmed AD target population.},
}

Humans
*Biomarkers/cerebrospinal fluid
*alpha-Synuclein/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnosis
Male
Female
Aged
Disease Progression
*Cognitive Dysfunction/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Lewy Body Disease/cerebrospinal fluid
Positron-Emission Tomography

@article {pmid41506537,
year = {2026},
author = {Liang, YZ and Jiang, MZ and Xu, XT and Zhu, T and Guo, H and Ding, L and Zhong, H and Bao, J and Qin, LQ and Li, YH},
title = {Ameliorating effect and mechanism of p-coumaric acid liposome on cognitive dysfunction and mitochondrial damage under intermittent hypoxia.},
journal = {Life sciences},
volume = {},
number = {},
pages = {124197},
doi = {10.1016/j.lfs.2026.124197},
pmid = {41506537},
issn = {1879-0631},
abstract = {AIMS: Alzheimer's disease (AD) has become a global public health problem. Mitochondrial dysfunction contributes to AD pathogenesis, and adequate oxygen supply is essential to maintain mitochondrial homeostasis. P-coumaric Acid (CA) is a polyphenol with anti-hypoxia and anti-AD properties. In this study, CA was formulated into a biomimetic liposome (CA-Lip) to enhance its therapeutic efficacy, and the underlying mechanisms were studied.

MATERIALS AND METHODS: APP/PS1 mice were divided into four groups: AD group, hypoxia treatment group (AD-HY group), hypoxia + CA treatment group (CA group), hypoxia + CA-Lip treatment group (CA-Lip group). Age-matched wild-type littermates were used as controls. Mice in the hypoxia treatment groups were exposed to a hypoxia chamber for 6 h daily for 8 weeks. Cognitive performance and mitochondrial function were subsequently evaluated to determine the ameliorating effects and mechanisms of CA-Lip.

RESULTS: Cognitive impairment and mitochondrial dysfunction were more pronounced in the AD-HY group than in the AD group. CA-Lip produced greater neuroprotective effects than CA. Mechanistic analyses showed that CA-Lip reduced amyloid-β (Aβ) accumulation, enhanced mitochondrial biogenesis (upregulation of PGC-1α expression), maintained mitochondrial dynamics (upregulation of MFN2 expression, and downregulation of Drp1 expression), inhibited excessive mitophagy (downregulation of PINK1 and Parkin expression), enhanced cell autophagy (upregulation of ATG7 and LC3B expression and downregulation of mTOR and P62 expression), and reduced neuronal apoptosis.

CONCLUSIONS: CA-Lip effectively ameliorates hypoxia-induced cognitive impairment by reducing Aβ generation and improving mitochondrial function.},
}

@article {pmid41506530,
year = {2025},
author = {Bali, D and Janelidze, S and Salvadó, G and Ashton, NJ and Palmqvist, S and Rodriguez, JL and Stomrud, E and Mattsson-Carlgren, N and Hansson, O},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105473},
doi = {10.1002/alz70856_105473},
pmid = {41506530},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Amyloid beta-Peptides/blood ; *tau Proteins/blood ; Aged ; Neurofilament Proteins/blood ; *Cognitive Dysfunction/blood ; Glial Fibrillary Acidic Protein/blood ; *Alzheimer Disease/blood ; Sweden ; Peptide Fragments/blood ; Longitudinal Studies ; Aged, 80 and over ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: Blood based biomarkers of Alzheimer´s disease (AD) that exhibit a high degree of change over time and are associated with deterioration in cognitive performance and atrophy could be useful in clinical trials to monitor treatment responses. In this study we investigated the longitudinal changes in plasma p-tau biomarkers, amyloid-beta(Aβ)42/Aβ40, Glial fibrillary acidic protein (GFAP) and Neurofilament light (NfL) and assessed associations between changes in these biomarkers and cognitive decline.

METHOD: We included 718 participants (cognitively unimpaired (CU) or Mild Cognitive Impairment (MCI)) from the Swedish BioFINDER-1 cohort who were followed upto 8 years. Plasma samples were analyzed for p-tau217 (Lilly immunoassay), NfL, GFAP, p-tau181 (Roche Prototype immunoassay), N-terminal tau (NTA-tau;Simoa immunoassay) and Aβ42/Aβ40 (mass spectrometry). We analyzed changes in individual plasma biomarker levels using linear mixed-effects models, incorporating Aβ status*time interaction. Associations between biomarker slopes and cognitive decline (assessed with mini-mental state examination [MMSE] and modified Preclinical Alzheimer´s Cognitive Composite[mPACC]) were assessed. An optimal model combining several biomarker slopes was also evaluated.

RESULT: In the whole cohort, p-tau217, NfL, GFAP and p-tau181 were significantly increased over time showing more accelerated increase in Aβ+ than Aβ- participants. The strongest effect was seen for p-tau217 (β=0.200, 95%CI0.17-0.23;p<0.001) followed by NfL(β=0.047, 95%CI0.015-0.08;p=0.005), GFAP(β=0.068, 95%CI0.046-0.09; p = <0.001) and p-tau181(β=0.089, 95%CI0.051,0.13;p<0.001)(Table 1, Figure 1). In individual models, slopes of all biomarkers were associated with change in MMSE and mPACC in the whole cohort. In the Aβ+ group, all biomarkers except NTA-tau demonstrated significant associations with longitudinal MMSE and mPACC. The strongest associations were seen for p-tau217 in both the whole cohort [MMSE (β=-0.353, 95%CI -0.40-(-0.31)]; for interaction between p-tau217 slope and time to predict cognitive scores; mPACC(β=-0.226 95%CI-0.26-(-0.19);p<0.001) and in the Aβ+ group [MMSE(β=-0.336, 95%CI-0.40-(-0.27); mPACC(β=-0.245, 95%CI-0.31-(-0.18);p<0.001)] (Tables 2-5). The best performing model for predicting longitudinal MMSE and mPACC included the interaction between p-tau217 slope (but not other biomarker slopes) and time, both in the whole cohort [MMSE(β=-0.340,95%CI -0.39-(-0.30)); mPACC(β=-0.238, 95%CI-0.27-(-0.20);p<0.001)] and in the Aβ+ group [MMSE(β=-0.327, 95%CI -0.40-(-0.25)]; mPACC(β=-0.263, 95%CI -0.32-(-0.20); p <0.001)].

CONCLUSION: The longitudinal changes in plasma p-tau217 might serve as a surrogate marker for monitoring some aspects of disease progression during treatment trials.},
}

Humans
*Biomarkers/blood
Male
Female
*Amyloid beta-Peptides/blood
*tau Proteins/blood
Aged
Neurofilament Proteins/blood
*Cognitive Dysfunction/blood
Glial Fibrillary Acidic Protein/blood
*Alzheimer Disease/blood
Sweden
Peptide Fragments/blood
Longitudinal Studies
Aged, 80 and over
Middle Aged
Cohort Studies

@article {pmid41506295,
year = {2025},
author = {Condado, JG and Klinger, HM and Birkenbihl, C and Elorriaga, IT and Seto, M and Coughlan, GT and Properzi, MJ and Yang, HS and Erramuzpe, A and Rentz, DM and Schultz, AP and Chhatwal, JP and Johnson, KA and Cortes, JM and Sperling, RA and Hohman, TJ and Donohue, MC and Diez, I and Buckley, RF},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106989},
doi = {10.1002/alz70856_106989},
pmid = {41506295},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Biomarkers/metabolism ; Aged ; Magnetic Resonance Imaging ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Positron-Emission Tomography ; *Brain/diagnostic imaging/pathology/metabolism ; *Cognitive Dysfunction/diagnostic imaging ; Longitudinal Studies ; *Aging/pathology ; Aged, 80 and over ; Cohort Studies ; Middle Aged ; Neuroimaging ; },
abstract = {BACKGROUND: BrainAge models estimate biological brain age based on neuroimaging data, providing a measure of brain health. This metric is particularly relevant in Alzheimer's disease (AD), where accelerated brain aging is exacerbated by β-amyloid (Aβ) and tau accumulation. We investigated the extent to which BrainAge moderates associations between AD biomarkers and longitudinal cognitive decline across two independent cohorts.

METHODS: We examined 1690 participants from A4/LEARN and 349 from HABS (Table 1). Using the Open-Source tool AgeML within each cohort, we built a BrainAge linear regressor model with 5-fold cross validation using MRI-T1 volumetric and FreeSurfer cortical thickness ROIs. We compared predicted ages with chronological age to create a BrainAgedelta. To avoid regressing out sex and APOEε4 variance, separate male/female models were built with data from APOEε4 non-carriers and applied to each cohort. We examined BrainAgedelta as a moderator of global neocortical Aβ-PET burden, temporal lobe Tau PET composite and p-tau217 associations with longitudinal PACC using linear mixed effects models. We adjusted for random intercepts and slopes, and baseline age, sex, years of education and APOEε4. In A4/LEARN we additionally adjusted for cumulative dose and treatment group using a spline model.

RESULTS: Higher levels of Aβ-PET, Tau-PET and p-tau217 at baseline was significantly correlated with higher BrainAgedelta (worse) (Figure 1). BrainAgedelta was directly associated with PACC trajectories in both cohorts. It also moderated the association between Aβ and Tau-PET and PACC trajectories such that higher BrainAgedelta was associated with faster cognitive decline with increasing levels of each biomarker. We found the same pattern of effects in p-tau217 limited only to the A4/LEARN sample but was trend-level in HABS (Figure 2).

CONCLUSIONS: BrainAgedelta is significantly associated with Aβ and tau burden and moderates their association with cognitive decline, supporting previous literature suggesting that BrainAge is a robust marker of brain health. Prioritizing individuals with worse BrainAge for clinical trials could not only effectively reduce screen fails (estimates forthcoming) but is a potentially feasible approach given that it can be calculated from a single T1-weighted MRI scan. These findings also highlight the importance of age-independent neurodegeneration patterns to contribute unique signal in models of brain health and pathological progression.},
}

Humans
Male
Female
Biomarkers/metabolism
Aged
Magnetic Resonance Imaging
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Positron-Emission Tomography
*Brain/diagnostic imaging/pathology/metabolism
*Cognitive Dysfunction/diagnostic imaging
Longitudinal Studies
*Aging/pathology
Aged, 80 and over
Cohort Studies
Middle Aged
Neuroimaging

@article {pmid41505775,
year = {2025},
author = {Saxena, S and Ye, Y and Devanarayan, V and Reyderman, L and Wildsmith, KR and Sachdev, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e106893},
doi = {10.1002/alz70856_106893},
pmid = {41505775},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/genetics ; *RNA, Long Noncoding/cerebrospinal fluid/genetics ; *Biomarkers/cerebrospinal fluid ; Male ; Female ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; *Peptides/cerebrospinal fluid ; },
abstract = {BACKGROUND: Long non-coding RNAs (lncRNAs) play a significant role in the pathogenesis of Alzheimer's disease (AD). They modulate various cellular processes such as amyloid production, Tau hyperphosphorylation, neuroinflammation, and the impairment of mitochondrial and synaptic functions. Emerging studies have revealed that certain lncRNAs can encode small open reading frame-derived peptides. However, the identification and understanding of the role of lncRNA-encoded peptides in AD remain largely unexplored due to the inherent low abundance and small sizes of these peptides. Here, we leveraged the de novo peptide sequencing algorithm and a custom database to identify lncRNA-encoded peptides in cerebrospinal fluid (CSF) of demented subjects METHOD: We developed an innovative strategy to identify lncRNA-encoded peptides in biofluids. A custom database of hypothetical peptides was generated by six-frame translation of all lncRNAs from LNCipedia (www.lncipedia.org) and integrated to human SwissProt protein entries. MS data (PRIDE archive PXD016278) from CSF of demented subjects with (n = 29) or without (n = 31) amyloid positivity were analyzed. Peptide raw peak area intensities were quantile normalized and log2 transformed to reduce technical variation and ensure distribution symmetry. Differentially expressed peptides were identified via analysis of covariance after adjusting for age and gender, with the significant criteria based on 20% false discovery rate (FDR).

RESULT: The de novo-assisted search of MS spectra identified 32,191 peptides at 0.1% global peptide-level FDR. Mapping of de novo peptides to our custom database identified 99 lncRNA-encoded peptides in CSF of demented subjects. 7/99 significantly (q<0.2; Cohens >0.8) altered lncRNA-encoded peptides were linked to amyloid positivity. These peptides were translated from non-coding regions of six lncRNA genes involved in the cellular processes relevant to AD, including tau protein aggregation and glutamatergic synapse plasticity.

CONCLUSION: This is the first study identifying differentially regulated lncRNA-encoded peptides in the CSF of Ab+ (AD) and Ab- (non-AD) dementia. Further investigation of novel lncRNA-derived peptides lights a new beacon to explore their promising applications in AD diagnosis, staging, and future treatment strategies.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/genetics
*RNA, Long Noncoding/cerebrospinal fluid/genetics
*Biomarkers/cerebrospinal fluid
Male
Female
Aged
Amyloid beta-Peptides/cerebrospinal fluid
*Peptides/cerebrospinal fluid

@article {pmid41505707,
year = {2025},
author = {Anwar, M and Landry, B and Wang, W and Alhasan, K and Yang, H and Fraser, R},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105281},
doi = {10.1002/alz70856_105281},
pmid = {41505707},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; Male ; Female ; Aged ; Proteomics/methods ; *Metabolomics/methods ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), a leading cause of dementia, poses a global health challenge as aging populations expand. Traditionally, practitioners rely on symptom-based identification, often miss the critical window for early intervention, limiting opportunities for improved clinical outcomes. Molecular You (MY) has developed an innovative, two-sided platform to address this gap. The platform i) quantifies 280 high-value plasma metabolites and proteins with absolute quantification and ii) through its algorithms ranks health risks and provides insights across more than 20 biological systems and pathways with an average predictive value of 88%. This study demonstrates the value of applying the MY platform in identifying AD risk and associated co-morbidities early, stratifying patients into endotype-specific mechanisms that inform customized care plans.

METHOD: Plasma samples from 74 patients, including 5 diagnosed with AD, were collected after an overnight fast, rapidly frozen, and shipped to MY for analysis. Each specimen underwent quantitative metabolomic (143 metabolites) and proteomic (140 proteins) assays using well-established LC-MS/MS methods. The resulting data were processed through the MY platform to identify health risks and map key biological pathways.

RESULT: Four of the five patients diagnosed with AD were confirmed, while one patient's profile was more aligned with vascular dementia. Additionally, 36 patients were identified at moderate to high risk for AD. Analysis of the biological pathways revealed several distinct endotypes for AD risk: dyslipidemia/ abnormal lipid metabolism, metabolic aberrations, inflammation and oxidative stress driving neuroinflammation and neurodegeneration, and neurotransmitter dysfunction leading to excitotoxicity and synaptic dysfunction. Several co-morbidities were identified in the population, including metabolic health issues such as diabetes, kidney health, liver health, immune health, cardiovascular disease, and inflammatory bowel disease. Personalized care plans were developed based on these findings, incorporating targeted dietary, lifestyle, and clinical interventions.

CONCLUSION: The MY platform demonstrates the feasibility of multi-omic analysis of blood to enhance the early detection of AD before clinical symptoms manifest, identify emerging co-morbidities, stratify patients into AD endotypes enabling precision preventative and personalized care. By monitoring patients longitudinally using the MY platform it will be possible to objectively quantify treatment efficacy, safety and overall patient outcomes.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/blood/diagnosis
Male
Female
Aged
Proteomics/methods
*Metabolomics/methods
Aged, 80 and over

@article {pmid41505448,
year = {2025},
author = {Steward, A and Dewenter, A and Roemer-Cassiano, S and Biel, D and Zhu, Z and Frontzkowski, L and Hirsch, F and Klonowksi, M and Gnörich, J and Dehsarvi, A and Brendel, M and Franzmeier, N},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105476},
doi = {10.1002/alz70856_105476},
pmid = {41505448},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/cerebrospinal fluid/metabolism/blood ; *Alzheimer Disease/genetics/diagnostic imaging/cerebrospinal fluid/metabolism ; Biomarkers/cerebrospinal fluid/blood ; Female ; Male ; *Apolipoprotein E4/genetics ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Aged ; Positron-Emission Tomography ; Aged, 80 and over ; Cross-Sectional Studies ; Alleles ; Brain/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: Understanding factors influencing Alzheimer's disease (AD) progression is crucial for optimising treatment timing and targets. A major genetic risk factor, the Apolipoprotein E ε4 allele (ApoE4), is associated with earlier tau pathology accumulation and spread at lower amyloid-beta (Aβ) levels (Steward, JAMA Neurol, 2023). However, the mechanisms underlying this association remain unclear (Figure 1A). Therefore, we assessed how ApoE4 accelerates Aβ-related tau aggregation. Specifically, we investigated whether ApoE4 promotes Aβ-driven secretion of phospho tau (p-tau) or ptau dependent tau aggregation, and determined whether ApoE4 promotes tau pathology in an allele dose-dependent manner.

METHOD: We analysed data from APOE-genotyped AD-spectrum participants in the ADNI (n = 201) and A4 cohorts (n = 200), integrating cross-sectional fluid biomarker measures (plasma ptau217, CSF ptau181) and longitudinal Flortaucipir tau-PET and Florbetaben/Florbetapir amyloid-PET. Using linear regression, we assessed whether the interaction between amyloid-PET and ApoE4 allele dosage influences plasma ptau217, and replicated this analysis with CSF ptau181 in an ADNI subset (n = 115). Secondly, to investigate whether ApoE4 enhances tau fibrilisation and spread, we calculated annual tau-PET SUVR accumulation rates across a connectivity-based tau spreading stages, using our prior methodology (e.g. Franzmeier, Sci Adv, 2020). Linear regressions tested the interaction between ptau217 (or CSF ptau181) and ApoE4 allele count on connectivity-mediated tau-PET accumulation in four connectivity stages that capture progressive tau spread.

RESULT: ApoE4 allele dosage did not moderate the relationship between amyloid-PET and plasma ptau217 in either sample (Figure 1B, ADNI: β=0.13, p = 0.32; A4: β=-0.20, p = 0.17) nor between amyloid-PET and CSF ptau181 in ADNI subsample (Figure 1B, b=-.16, p = 0.42). However, a significant ApoE4 allele dose effect was observed in moderating the relationship between plasma ptau217 and tau-PET accumulation across connectivity stages independent of amyloid burden (Figure 1C, ADNI: Q1-4 mean β=0.44, Q1-4 p <0.001; A4: Q1-4 mean β = 0.56, Q1,2,4 p <0.001, Q3 p <0.05), with the strongest effect in individuals carrying two ApoE4 alleles.

CONCLUSION: ApoE4 exerts an allele dose-dependent effect on ptau induced tau aggregation, driving accelerated tau spreading at lower Aβ levels. This suggests that attenuating soluble ptau increases in ApoE4 carriers may mitigate downstream tau fibrilisation and delay dementia onset, highlighting the potential of personalised therapeutic approaches.},
}

Humans
*tau Proteins/cerebrospinal fluid/metabolism/blood
*Alzheimer Disease/genetics/diagnostic imaging/cerebrospinal fluid/metabolism
Biomarkers/cerebrospinal fluid/blood
Female
Male
*Apolipoprotein E4/genetics
Amyloid beta-Peptides/metabolism/cerebrospinal fluid
Aged
Positron-Emission Tomography
Aged, 80 and over
Cross-Sectional Studies
Alleles
Brain/diagnostic imaging/metabolism

@article {pmid41505228,
year = {2026},
author = {Head, E and Cohen, A and Fortea, J and McGlinchey, E},
title = {Novel insights into Alzheimer's disease through the study of individuals with Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71074},
doi = {10.1002/alz.71074},
pmid = {41505228},
issn = {1552-5279},
support = {U19AG068054//NIH/NIA/ ; U19AG068054//NIH/NIA/ ; P30AG066519//NIH/NIA/ ; RF1AG079519//NIH/NIA/ ; U19AG068054//NIH/NIA/ ; P30AG066519//NIH/NIA/ ; RF1AG079519//NIH/NIA/ ; R01AG056850//NIH/NIA/ ; R21AG056974//NIH/NIA/ ; R01AG061566//NIH/NIA/ ; 1R01AG081394//NIH/NIA/ ; R61AG066543//NIH/NIA/ ; //Fondo de Investigaciones Sanitario/ ; INT21/00073//Carlos III Health Institute/ ; PI20/01473//Carlos III Health Institute/ ; PI23/01786//Carlos III Health Institute/ ; //Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Program 1/ ; //Fondo Europeo de Desarrollo Regional/ ; SLT006/17/00119//Department de Salut de la Generalitat de Catalunya/ ; //Fundación/ ; IIBSP-DOW-2020-151//Tatiana Pérez de Guzmán el Bueno/ ; H2020-SC1-BHC-2018-2020//Horizon 2020-Research and Innovation Framework Programme/ ; HPE-ADRD 24HPE1284307//Alzheimer Association/ ; },
}

@article {pmid41505225,
year = {2025},
author = {Ramirez-Galvan, FA and Jimenez-Galaviz, DA and Padilla-Mendoza, JR and Jijon-Lorenzo, R and Silva-Lucero, MD and Cardenas-Aguayo, MD},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105315},
doi = {10.1002/alz70856_105315},
pmid = {41505225},
issn = {1552-5279},
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/blood/complications ; Biomarkers/blood ; Male ; *Cognitive Dysfunction/blood/metabolism ; Female ; Autophagy/drug effects ; Aged ; Metformin/pharmacology ; Glycated Hemoglobin/metabolism ; Middle Aged ; Hypoglycemic Agents/pharmacology ; },
abstract = {BACKGROUND: Type 2 Diabetes (T2D) is highly prevalent in Latin America, particularly in Mexico, with 15.6% of the population affected (ENSANUT 2020, Montoya 2023). T2D increases the risk of complications: hypertension and dementia. Mild Cognitive Impairment (MCI) precedes Alzheimer's dementia, the most common type. Metformin, the primary treatment for T2D, enhances autophagy, a cellular process for recycling primary components. Autophagy impairment is linked to dementia (Nixon 2024). This study utilizes human olfactory neuroepithelial precursor cells (hONE-NPCs) as a model for neurodegeneration. Olfactory dysfunction is an early indicator of dementia, suggesting that alterations in hONE-NPCs may reflect early stages of the disease.

METHOD: This study included four groups: healthy controls, individuals with cognitive impairment, those with T2D, and with T2D and cognitive impairment (T2D-MCI). hONE NPCs were isolated from each participant and characterized using Western Blotting and immunocytofluorescence. Blood samples were collected for HbA1c and protein samples for autophagy markers. Participants underwent a MoCA Test by a certified applicator (MXRAMFR710802563-01), a medical interview to assess metformin treatment history, and an olfactory test. hONE-NPCs were treated with or without metformin for 24 hours. Protein samples were collected for Western Blotting analysis in three groups in vitro: Diabetes+MCI+Metformin, Diabetes-MCI-Metformin, and Control+Metformin.

RESULT: Culture cells hONE-NPCs from Diabetes+MCI and Pre-Diabetic+MCI from patients that had been treated with metformin and their cells were treated with metformin show an impairment in the autophagy flux since p62 was elevated and LC3-II was downregulated. Conversely, culture cells from control individuals who had never been treated with metformin responded to metformin in vitro treatment with an increase in autophagy flux, showing p62 reduction and an increase in LC3-II.

CONCLUSION: Our results suggest a preconditioning effect of hONE-NPCs from patients receiving metformin treatment on their response to this drug in vitro. Cells from patients who were prescribed metformin show an impairment in the autophagy flux; however, culture hONE.NPCs cells from control individuals who had never been treated with metformin responded to metformin in vitro treatment with an increase in autophagy flux. This finding may have clinical implications in the long-term effects of metformin treatment in peripheral cells as a systemic effect.},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy/blood/complications
Biomarkers/blood
Male
*Cognitive Dysfunction/blood/metabolism
Female
Autophagy/drug effects
Aged
Metformin/pharmacology
Glycated Hemoglobin/metabolism
Middle Aged
Hypoglycemic Agents/pharmacology

@article {pmid41505203,
year = {2026},
author = {Lyketsos, CG and Peters, ME},
title = {Neuropsychiatric symptoms in Alzheimer's disease: Past, present, and future.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71077},
doi = {10.1002/alz.71077},
pmid = {41505203},
issn = {1552-5279},
support = {P30AG066507//Johns Hopkins Alzheimer's Disease Research Center/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/complications ; *Cognitive Dysfunction/psychology ; Disease Progression ; *Depression/etiology ; },
abstract = {Noncognitive neuropsychiatric symptoms (NPS; e.g., depression, agitation) are nearly universal throughout the course of Alzheimer's disease (AD), cause significant adverse impact to patients and caregivers, and are associated with more rapid progression to severe dementia. Although the importance and presence of NPS was recognized by Dr. Alois Alzheimer himself, it was a series of research roundtables in the 2010s that propelled the understanding and treatment of NPS in AD forward. The mild behavioral impairment (MBI) construct was developed as a complementary behavioral analogue to mild cognitive impairment, solidifying the importance of NPS prior to dementia onset. Neurobiological underpinnings of NPS are being studied and the NPS treatment pipeline includes novel therapeutics, repurposing of existing pharmaceuticals, and non-pharmacologic interventions. The Alzheimer's Disease Research Centers and The National Alzheimer's Coordinating Center, being recognized in this special issue, have played a pivotal role in the recognition and study of NPS in AD. HIGHLIGHTS: Noncognitive neuropsychiatric symptoms (NPS) are nearly universal throughout the course of Alzheimer's disease (AD), cause significant adverse impact to patients and caregivers, and are associated with more rapid progression to severe dementia. A series of research roundtables in the last decade and a half have propelled the understanding and treatment of NPS in AD forward. The mild behavioral impairment (MBI) construct was developed as a complementary behavioral analogue to mild cognitive impairment, solidifying the importance of NPS prior to dementia onset. Neurobiological underpinnings of NPS are being studied and the treatment pipeline includes novel therapeutics, repurposing of pharmaceuticals, and non-pharmacologic interventions. The Alzheimer's Disease Research Centers and The National Alzheimer's Coordinating Center have played a pivotal role in the recognition and study of NPS in AD.},
}

Humans
*Alzheimer Disease/psychology/complications
*Cognitive Dysfunction/psychology
Disease Progression
*Depression/etiology

@article {pmid41505171,
year = {2025},
author = {Coughlan, GT and Klinger, HM and Seto, M and Birkenbihl, C and Li, A and Farrell, ME and Thibault, EG and Properzi, MJ and Schultz, AP and Townsend, DL and Langford, O and Chhatwal, JP and Yang, HS and Raman, R and Donohue, MC and Johnson, KA and Sperling, RA and Buckley, RF},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106874},
doi = {10.1002/alz70856_106874},
pmid = {41505171},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/blood/metabolism ; Male ; Female ; *Biomarkers/blood ; Aged ; Positron-Emission Tomography ; *Amyloid beta-Peptides/blood/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Longitudinal Studies ; *Brain/metabolism/diagnostic imaging ; Middle Aged ; Peptide Fragments/blood ; Aged, 80 and over ; Phosphorylation ; },
abstract = {BACKGROUND: The pathophysiological cascade of Alzheimer's Disease(AD) is characterized by amyloid-β(Aβ) related secretion of soluble phosphorylated tau (p-tau), followed by aggregation of tau tangles and subsequent cognitive decline. Previous literature suggests that tau proliferation is more aggressive at younger ages, but the extent to which this is true and can be detected by plasma markers remains unclear. We examined whether age interacts with plasma p-tau217 and p-tau217/Aβ42 and to predict rates of regional tau-PET accumulation in baseline clinical normal adults.

METHOD: Participants were 578 clinically normal individuals (mean age 72.2; 295 APOEε4-carriers [56%]; mean years of education 16.3) with baseline plasma p-tau217 and longitudinal tau-PET from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study as well as the Alzheimer's Disease Neuroimaging Initiative. Medial temporal lobe (amygdala, parahippocampal gyrus, entorhinal cortex) and neocortical (inferior parietal, fusiform, inferior temporal) tau composites were chosen as longitudinal tau-PET outcomes. The average tau-PET follow-up time was 3.5 years (SD=1.6 years, range=1.3-7.1 years). Random-effects regression estimated the interaction between baseline age and baseline p-tau217 longitudinal tau composites, adjusting for sex and years of education (including participant-specific intercepts and slopes).

RESULT: In A4/LEARN, age moderated the association between plasma p-tau217 and neocortical tau accumulation (β=-0.06, =-0.09 - -0.04, p <0.001; Figure 1A), such that the effects of elevated p-tau217 on tau were stronger at younger ages. Similarly in ADNI, age moderated the association between p-tau217/Aβ42 and neocortical tau accumulation (β=-0.12, =-0.18 - -0.06, p <0.001;Figure 1B, such that the effects of elevated p-tau217/Aβ42 on tau accumulation were stronger at younger ages. The raw tau trajectories for one neocortical region as a function of age and p-tau217 is illustrated in Figure 1C. In Post-hoc analysis covarying APOEε4 status, the interactive effects of age and p-tau217 remained significant.

CONCLUSION: There is evidence for more aggressive tau-related processes in younger individuals. These findings highlight the critical need for early identification and enrollment in AD clinical trials, potentially using plasma biomarkers in primary care and secondary care.},
}

Humans
*tau Proteins/blood/metabolism
Male
Female
*Biomarkers/blood
Aged
Positron-Emission Tomography
*Amyloid beta-Peptides/blood/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Longitudinal Studies
*Brain/metabolism/diagnostic imaging
Middle Aged
Peptide Fragments/blood
Aged, 80 and over
Phosphorylation

@article {pmid41504713,
year = {2025},
author = {Marcatti, M and Fracassi, A and Zhang, W and Kayed, R and Taglialatela, G},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106869},
doi = {10.1002/alz70856_106869},
pmid = {41504713},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; *tau Proteins/blood/metabolism ; Male ; *Cognitive Dysfunction/blood/diagnosis ; Female ; Amyloid beta-Peptides/blood ; Aged ; *Extracellular Vesicles/metabolism ; *Brain/metabolism/pathology ; Aged, 80 and over ; Longitudinal Studies ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most common forms of dementia worldwide, making the identification of predictive biomarkers critical for early diagnosis and treatment during the preclinical stage. Recent studies have focused on blood-based biomarkers, particularly plasma brain-derived extracellular vesicles (pl-BDEVs), to detect central nervous system (CNS) alterations. While blood biomarkers like amyloid proteins (Aβ42/Aβ40), tau, and phosphorylated tau show diagnostic promise, identifying predictive biomarkers remains essential. Blood total-tau, originating from non-brain sources, highlights the need to analyze brain-derived tau (BDT) in pl-BDEVs as a more specific biomarker for AD and other neurodegenerative diseases. Longitudinal studies offer great potential for detecting preclinical biomarker patterns in at-risk individuals, yet little attention has been given to oligomers, the most toxic species in AD METHOD: In this study, we enriched pl-BDEVs from CNS cell types from plasma samples longitudinally collected from participants enrolled in the Texas Alzheimer's Research and Care Consortium (TARCC), who were initially cognitively normal or displayed mild cognitive impairment (MCI), and later either progressed to AD (termed "converters") or remained cognitively normal/MCI (termed "non-converters"). We evaluated the isolated pl-BDEVs by nanoparticle tracking analysis (size, number, and distribution), western blot (expression of extracellular vesicles markers: CD63, CD9, CD81), and electron microscopy. We immunoprecipitated brain-derived tau oligomers (BDTOs) from pl-BDEVs and characterized them by western blot, proteinase K (PK) digestion, seeding assay, and atomic force microscopy (AFM). Additionally, we treated SH-SY5Y neuroblastoma cells and human synaptosomes isolated from cortex of control samples with these BDTOs and assessed their cytotoxicity and synaptotoxicity, respectively.

RESULT: We demonstrated the successful isolation of pl-BDEVs from plasma samples and the detection of BDTOs within these pl-BDEVs. We identified distinct PK digestion patterns, morphology, and toxicity between BDTOs from converters and non-converters. Additionally, our data revealed different distribution of BDTOs in the pl-BDEVs isolated from the two groups. These findings suggest the presence of two different BDTO strains for converters and non-converters.

CONCLUSION: This study addresses the need for predictive AD biomarkers by analyzing previously unexplored BDTO conformers in pl-BDEVs. Discovering distinct BDTOs in peripheral brain derived extracellular vesicles could enable preclinical forecasting and advance early-stage AD treatments.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/blood/diagnosis
*tau Proteins/blood/metabolism
Male
*Cognitive Dysfunction/blood/diagnosis
Female
Amyloid beta-Peptides/blood
Aged
*Extracellular Vesicles/metabolism
*Brain/metabolism/pathology
Aged, 80 and over
Longitudinal Studies

@article {pmid41502736,
year = {2025},
author = {Biswal, B and Pattnaik, S and Satapathy, BS and Maharana, L},
title = {Luliconazole-Loaded Nanoliposomes as a Repurposing Strategy to Combat Memory Dysfunction in LPS-Induced Alzheimer's Rats.},
journal = {ACS omega},
volume = {10},
number = {48},
pages = {59655-59674},
pmid = {41502736},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder with no definitive cure. Out of several proposed pathophysiology, microbial infection has recently been identified as one of the key pathogenic contributors for the development and progression of AD. In this context, the present study aims at a repurposing strategy through luliconazole (a potent imidazole derivative)-loaded optimized nanoliposomal carriers to treat AD. Optimized luliconazole-loaded nanoliposomes (LuNLs) were developed by the conventional thin-film hydration method followed by characterization in terms of FESEM, AFM, zeta potential, average size, loading %, and drug release (in vitro). The in vivo effectiveness of the LuNLs was investigated in LPS-induced AD rats. Molecular docking and simulation analysis demonstrated a favorable docking score between luliconazole and selected AD proteins. Spherical, nanosized (52.42 nm), negatively charged (-29.9 mV) LuNLs were reported showing a sustained drug release up to 24 h. An in vivo behavioral study depicted improved cognitive behavior in the LuNLs-treated group as compared to control groups. In vivo antioxidant activity in terms of SOD, MDA, and GSH inhibition by LuNLs was found comparable to that of standard formulation-treated groups, depicting the neuroprotective behavior of LuNLs. The histopathological observation of brain tissue in the LuNLs/control group further substantiated the in vivo behavioral study data. Based on the reports, luliconazole may be used as a viable, efficacious alternative for the treatment of AD, though further preclinical studies are highly warranted.},
}

@article {pmid41502722,
year = {2025},
author = {Wu, H and Huang, N and Wang, K and Mi, J and Liu, Z and Wang, J and Sang, Z and Tan, Z},
title = {Development of Novel 3‑Phenylpropanamide Derivatives as BChE Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {ACS omega},
volume = {10},
number = {48},
pages = {59522-59534},
pmid = {41502722},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative degenerative disorder among the elderly, featured by progressive cognitive decline and memory impairment. Due to its complex pathogenesis, there is still no effective therapeutic drug to date. Recently, selective BChE inhibition has been regarded as a potent approach for treating AD. In this work, we conducted structural optimization and structure-activity relationship studies on the previously obtained lead compound EMC-4f, and obtained the potential selective BChE inhibitor 12a (eqBChE, IC50 = 1.3 μM; huBChE, IC50 = 0.95 μM). The in vitro results exhibited that 12a showed good BBB permeability. Moreover, 12a demonstrated significant neuroprotective effects on l-Glu/Aβ25-35-induced HT22 cells injury. Further, the in vivo tests suggested that 12a remarkably alleviated mice cognitive impairment induced by scopolamine. Therefore, these data present that 12a is a promising BChE inhibitor against AD.},
}

@article {pmid41502346,
year = {2026},
author = {Chang, YY and Zheng, XH and Wang, MW and Zhang, QW and Gao, YT and Wang, YN and Sun, YT and Fan, HH and Li, X and Du, LD and Xie, XM and Pang, XB},
title = {Morroniside Modulates Microglia Polarization via the CX3CL1/CX3CR1/PU.1 Axis in ApoE4 Transgenic Mice.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70177},
pmid = {41502346},
issn = {1099-1573},
support = {251111313400//Key R&D Program of Henan Province/ ; 252300421379//Natural Science Foundation of Henan/ ; 25B350004//Key Scientific Research Projects of Henan Higher Education Institutions/ ; 82501727//Natural Science Foundation of China/ ; 22508091//Natural Science Foundation of China/ ; },
abstract = {Microglia monitor disease stimulation, neuronal apoptosis, and neural repair, and their overactivation-induced inflammation plays a key role in the pathogenesis of Alzheimer's disease (AD). Morroniside (Mor), an iridoid glycoside compound in Cornus officinalis, is one of the effective active components. The effects of Mor on antioxidant stress, antiapoptosis, and nerve repair function have been widely studied, but the mechanism of Mor in AD treatment remains unclear. To study the neuroprotective effects of Mor and elucidate the molecular mechanisms underlying its improvement of AD symptoms, we used ApoE4 transgenic mice and ApoE4-transfected BV2 cells as models of AD, focusing on microglia phenotype, function, and neuroinflammation. The 10-month-old mice were randomly divided into the ApoE3 control group (ApoE3 + Veh), the ApoE4 model group (ApoE4 + Veh), and the ApoE4 + Mor 10, 20, and 40 mg/kg groups as in vivo models. The in vitro BV2-ApoE model was constructed via lentiviral transfection. The effects of Mor on cognitive function of AD models were assessed through behavioral tests, western blot, immunofluorescence staining, and ELISA to measure changes of related pathological and inflammatory factors. Mor improved the cognitive function of ApoE4 transgenic mice by reducing Aβ plaques in the brain, improving the structural lesions of hippocampal neurons, and increasing synaptic plasticity in the brain of AD mice. In addition, Mor promoted the transformation of microglia from the M1 to the M2 phenotype, inhibited the activation of the CX3CR1/PU.1 signaling axis, and alleviated the dysfunction of microglia both in vitro and in vivo. CX3CR1 siRNA and PU.1 siRNA were used further to verify the regulatory effect of Mor on microglia phenotype. Our findings indicate that Mor can inhibit neuroinflammation, reduce Aβ accumulation, and improve synaptic damage in ApoE4 mice via the CX3CL1/CX3CR1/PU.1 pathway regulating the phenotype and function of microglia. This study provides a new therapeutic candidate for the prevention and treatment of AD.},
}

@article {pmid41502301,
year = {2026},
author = {Abhyankar, SD and Xiao, Y and Mahajan, N and Luo, Q and Cummins, TR and Oblak, AL and Lamb, BT and Corson, TW and Bhatwadekar, AD},
title = {Müller Glial Kir4.1 Channel Dysfunction in APOE4-KI Model of Alzheimer's Disease.},
journal = {Glia},
volume = {74},
number = {3},
pages = {e70119},
doi = {10.1002/glia.70119},
pmid = {41502301},
issn = {1098-1136},
support = {R01EY027779-S1/EY/NEI NIH HHS/United States ; R01EY032080/EY/NEI NIH HHS/United States ; //Research to Prevent Blindness, Unrestricted Grant/ ; DK064466/DK/NIDDK NIH HHS/United States ; G20240315-8762//Sigma Xi Grants in Aid of Research/ ; //NIH T32, Peter J. Roach Award, Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine/ ; },
mesh = {Animals ; *Potassium Channels, Inwardly Rectifying/metabolism/genetics ; *Alzheimer Disease/metabolism/genetics/pathology ; *Ependymoglial Cells/metabolism/pathology/drug effects ; *Apolipoprotein E4/genetics/metabolism ; Kcnj10 Channel ; Disease Models, Animal ; Mice, Transgenic ; Rats ; Mice ; Mitochondria/metabolism ; Oxidative Stress/physiology ; Retina/metabolism/pathology ; Mice, Inbred C57BL ; },
abstract = {Alzheimer's disease (AD), particularly late-onset AD (LOAD), affects millions worldwide, with the apolipoprotein ε4 (APOE4) allele being a significant genetic risk factor. Retinal abnormalities are a hallmark of LOAD, and our recent study demonstrated significant age-related retinal impairments in APOE4-knock-in (KI) mice, highlighting that retinal impairments occur before the onset of cognitive decline in these mice. Müller cells (MCs), key retinal glia, are vital for retinal health, and their dysfunction may contribute to retinal impairments seen in AD. MCs maintain potassium balance via specialized inwardly rectifying K[+] channels 4.1 (Kir4.1). This study posits that Kir4.1 channels will be impaired in APOE4-KI, resulting in MC dysfunction. Additionally, we demonstrate that MC dysfunction in APOE4-KI stems from alterations in mitochondrial dynamics and oxidative stress. Kir4.1 expression and function were studied using immunofluorescence and through the whole-cell voltage clamp, respectively. In parallel, rat Müller cells (rMC-1) were used to create an in vitro model for further mechanistic studies. MitoQ was used to evaluate its potential to mitigate APOE4-induced deficits. APOE4 retinas and APOE4-transfected rMC-1 significantly reduced Kir4.1 expression, K+ buffering capacity, and increased mitochondrial damage. APOE4-transfected rMC-1 showed reduced mitochondrial membrane potential (ΔΨm) and increased mitochondrial reactive oxygen species (ROS). MitoQ treatment significantly reduced mitochondrial ROS and restored Kir4.1 expression in APOE4-expressing cells. Our results demonstrate that APOE4 causes mitochondrial dysfunction and MC impairment, which may contribute to retinal pathology in AD. MitoQ restored mitochondrial health and Kir4.1 expression in APOE4-expressing rMC-1, suggesting targeting mitochondria may offer a promising therapeutic strategy for AD.},
}

Animals
*Potassium Channels, Inwardly Rectifying/metabolism/genetics
*Alzheimer Disease/metabolism/genetics/pathology
*Ependymoglial Cells/metabolism/pathology/drug effects
*Apolipoprotein E4/genetics/metabolism
Kcnj10 Channel
Disease Models, Animal
Mice, Transgenic
Rats
Mice
Mitochondria/metabolism
Oxidative Stress/physiology
Retina/metabolism/pathology
Mice, Inbred C57BL

@article {pmid41501928,
year = {2026},
author = {Li, E and Song, F and Coppola, Q and Yack, L and Le, M and Javed, S and Pandher, N and Prufer, I and Mayzel, O and Heuer, HH and Koestler, M and Miller, BL and Boxer, AL and Vandevrede, L and Grinberg, LT and Walsh, CM and Neylan, TC},
title = {Treatment of Disturbed Sleep in Progressive Supranuclear Palsy: a randomized, remote, double-blinded, 6-week cross-over design study protocol comparing zolpidem, suvorexant, and placebo.},
journal = {Trials},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13063-025-09382-9},
pmid = {41501928},
issn = {1745-6215},
support = {A130340//Rainwater Charitable Foundation/ ; },
abstract = {BACKGROUND: Prior research identified profound sleep disruption in progressive supranuclear palsy (PSP). The hypothalamus and brainstem, areas that help regulate sleep/wake patterns, are among the earliest affected brain regions in PSP disease progression. Comparing polysomnography and quantitative-neuropathology metrics, we identified relative sparing of wake-promoting nuclei in PSP compared to Alzheimer's disease, though PSP had more disrupted sleep. It led to the hypothesis that PSP patients have hyperinsomnia (or hyposomnia, little sleep) due to degeneration of sleep nuclei with a preservation of sleep neurons, causing a system unbalance. A higher neuronal count of wake-promoting nuclei was associated with greater nocturnal wake, regardless of disease. Specifically, orexinergic wake-promoting neurons in the lateral hypothalamus, previously described as the sleep-on/off switch, are relatively spared in PSP. Thus, we hypothesized that an orexinergic antagonist may be more effective in treating sleep/wake issues in PSP than other hypnotic medications. This study protocol was established to test the safety and efficacy of an orexinergic antagonist (suvorexant) targeting the wake-promoting system and contrasts it with a GABAergic receptor agonist (zolpidem) targeting sleep-promoting systems and placebo.

METHODS: This is a remote clinical trial, designed as a double-blind, cross-over, within-subject 6-week trial, with 3 one-week-long conditions, separated by 1-week washout periods. The order of the 3 regimens is randomized and counterbalanced: placebo (microcrystalline cellulose), 15 mg/day suvorexant, 5 mg/day zolpidem. Participants are recruited from doctor and study referrals, registries, and support groups. Once onboarded, the trial coordinator maintains communication with the participant/caregiver throughout the 6 weeks. Assessments include neurological interviews, cognitive testing, and subjective questionnaire packets. Sleep and circadian rhythms are assessed through ambulatory EEG and actigraphy monitoring devices worn by the participant throughout the trial.

DISCUSSION: The study design aims to reduce participant and caregiver burden, while improving accessibility to such a study. Administering a remote clinical trial for a rare disease, however, creates unique issues that would otherwise be absent from in-person studies. Particularly, a symptom rather than disease-modifying trial is challenging to recruit for when potential disease-modifying therapeutics are available. Needing to coordinate with non-associated medical offices to attain medical records or prescriptions can cause frustrations for the potential participant, medical office, and study team. In recruitment, onboarding, and trial maintenance, this study design relies on consistent communication to support participant enrollment and satisfaction.

TRIAL REGISTRATION: Treatment of Disturbed Sleep in Progressive Supranuclear Palsy (PSP); NCT04014389. Registered on June 2, 2019.},
}

@article {pmid41469664,
year = {2025},
author = {Yu, X and Xiao, H and Bao, S and Dong, Y and Dong, Z and Zhao, J and Wang, G and Meng, X and Wang, F},
title = {Cigarette smoke-induced lung-brain barrier dysfunction drives neurocognitive impairment via inflammatory spill-over.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {10},
pmid = {41469664},
issn = {1742-2094},
support = {2024CX129//the Graduate Innovation Fund of Jilin University/ ; Not applicable//the Medical Basic Research Innovation Center of Airway Disease in North China/ ; Not applicable//Key Laboratory of Pathobiology/ ; 20200601011JC//Key Laboratory of Precision Infectious Diseases, Jilin Province/ ; 2022C036//Engineering Laboratory for Precision Prevention and Treatment of Common Diseases, Jilin Province/ ; 20230204055YY//Department of Science and Technology of Jilin Province: Key Scientific and Technological Research and Development Projects/ ; },
abstract = {BACKGROUND: Although the association between cigarette smoke (CS)-induced chronic obstructive pulmonary disease (COPD) and neurocognitive disorders is recognized, the underlying mechanisms remain unclear. To date, no studies have linked alterations in lung and brain barrier permeability to the “spill-over” of inflammatory factors in CS induced COPD-related neurocognitive disorders (COPD-NCDs).

METHODS: Using GWAS data, a two-sample Mendelian randomization (MR) analysis was conducted to explore the genetic associations between COPD and neurocognitive disorders (dementia, Alzheimer’s disease, etc.). A BALB/c female mouse model with CS exposure (9 cigarettes/day × 24 weeks) was established. Cognitive functions were evaluated using open field tests, novel object recognition tests, and Morris water maze tests. Histopathological changes were observed by HE and Masson staining. Cellular and molecular profiles in brain tissues were analyzed by single-cell RNA sequencing. Levels of inflammatory factors were detected by ELISA. Barrier permeability changes in the lungs and brain were assessed by using Evans Blue staining. Tight junction proteins in lung and brain tissues were measured by immunofluorescence and Western blotting.

RESULTS: MR analysis revealed causal associations between COPD and Alzheimer’s disease, dementia, depression, anxiety, and Parkinson’s disease. CS-exposed mice exhibited COPD phenotypes (emphysema, reduced lung function) and cognitive impairments (memory deficits, anxiety-like behaviors). Activation of microglia/astrocytes and decreased neuronal/synaptic marker expression were observed in the hippocampus. Increased leakage of Evans blue staining in the lungs and brain, along with downregulated expression of tight junction proteins (Occludin, Claudin1, ZO-1), indicated increased blood-brain barrier (BBB) permeability. Elevated levels of inflammatory factors (IL-1β, IL-6, TNF-α) were detected in lung tissues, brain tissues and serum.

CONCLUSIONS: CS exposure disrupts lung barrier function, leading to the “spill-over” of inflammatory factors to the brain via the lung-brain axis. This increases BBB permeability, triggering neuroinflammation, impairing hippocampal neuronal and synaptic function, and ultimately causing neurocognitive disorders. This study elucidates a novel mechanism of COPD-NCDs, which may provide new targets for the treatment of COPD-NCDs.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03629-7.},
}

@article {pmid41501420,
year = {2026},
author = {Wang, XY and Zhou, WS and Gaur, U and Zhen, XC and Zheng, WH},
title = {Sigma-1 receptor positive allosteric modulator promotes neuronal survival and improves cognitive deficits in AD mice via sigma-1 receptor/ERK pathway.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {41501420},
issn = {1745-7254},
abstract = {The sigma-1 receptor is an important new therapeutic drug target for Alzheimer's disease (AD). Here, we reported that SOMCL-668, a novel selective and potent sigma-1 receptor allosteric modulator, is neuroprotective in AD both in vitro and in vivo. SOMCL-668 promoted PC12 cells against Aβ-induced intracellular reactive oxygen species (ROS) accumulation, mitochondrial membrane potential hyperpolarization and neuronal apoptosis. Similar results were obtained in SH-SY5Y and primary cortical culture neurons. The mechanistic study showed that SOMCL-668 stimulated the phosphorylation of ERK and CREB, while pharmacological inhibition or knockout of ERK via CRISPR-Cas9 attenuated its protective effects. Further studies with the sigma-1 receptor agonists/antagonists and knockout of sigma-1 receptor via CRISPR-Cas9 indicated that the sigma-1 receptor is essential for the effect of SOMCL-668. In 3xTg-AD mice, SOMCL-668 improved the learning and memory deficits, inhibited neuronal apoptosis and oxidative stress, reduced Aβ deposition and tau protein phosphorylation via ERK/CREB pathway. Moreover, pretreatment with sigma-1 receptor antagonist BD1047 blocked the effect of SOMCL-668. These results demonstrated that SOMCL-668 provides neuroprotection in AD and its effect is mediated by the sigma-1 receptor/ERK/CREB pathway. Our findings support that SOMCL-668 can be utilized as a potential drug for the prevention and treatment of Alzheimer's disease.},
}

@article {pmid41500848,
year = {2025},
author = {Prabha, PK and Jain, A and Dadoo, N and Charan, S and Medhi, B and Prakash, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105361},
doi = {10.1002/alz70856_105361},
pmid = {41500848},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnosis ; *Biomarkers/blood ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Cholesterol/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition marked by memory loss, cognitive decline, and eventually motor and behavioural dysfunction. Most AD drug trials have failed due to the lack of early intervention, which is crucial for treatment effectiveness. Though early diagnosis remains challenging owing to blood-brain barrier, blood-based biomarkers are being explored due to their non-invasive nature. Genes involved in cholesterol and lipid metabolism, such as APOE, APOJ, ABCA7, and SORL1, have also been observed to increase AD risk.

METHODS: Clinical studies of polymorphisms in cholesterol homeostasis pathway involving participants clinically diagnosed with Alzheimer's Disease of any form as per set criteria of diagnosis for AD were included after comprehensive search across PubMed, Embase, Scopus and Web of Science. Independent reviewers extracted data from the included studies which included information like general information, participants, study methods, polymorphisms studied, outcomes, results, conclusion, etc. Any discrepancies or doubts was resolved by a third reviewer.

RESULT: A total of 1870 studies were identified based on the designed search strategy, which reduced to 216 after removal of duplicates, with 45 studies considered suitable for the final meta-analyses. The risk of AD was significantly associated in random effect model for SNP rs3846662 (HMGCR; OR = 1.16, 95% CI = 0.99, 1.35, I[2] = 59%, p = 0.06), rs11136000 (CLU; OR = 1.15, 95% CI = 1.08, 1.22, I[2] = 0%, p = 0.83), rs754203 (CYP46A1; OR = 1.10, 95% CI = 0.92, 1.33, I[2] = 87%, p < 0.01), and rs3851179 (PICALM; OR = 1.18, 95% CI = 1.05, 1.33, I[2] = 77%, p < 0.01).

CONCLUSION: The selected SNPs were found to be significantly associated with the risk of AD, with risk alleles for rs3846662, rs11136000, rs754203, and rs3851179 being G, C, T, C alleles respectively with an OR of 1.16, 1.15, 1.10, and 1.18 respectively. Therefore, these can be considered to be AD biomarkers.},
}

Humans
*Alzheimer Disease/genetics/diagnosis
*Biomarkers/blood
Polymorphism, Single Nucleotide
Genetic Predisposition to Disease
Cholesterol/metabolism

@article {pmid41500650,
year = {2025},
author = {Tirambulo, CVG and Merlini, S and Paul, M and Lizarraga, C and Brinton, RD and Vitali, F},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105280},
doi = {10.1002/alz70856_105280},
pmid = {41500650},
issn = {1552-5279},
mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; *Alzheimer Disease/blood/genetics/diagnosis ; Aged ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Middle Aged ; Apolipoprotein E4/genetics ; Registries ; Risk Factors ; },
abstract = {BACKGROUND: Individuals in the early stages of Alzheimer's disease (AD) constitute a heterogeneous group, with diverse risk factor profiles such as chromosomal sex, apolipoprotein E (APOE) genotype, and comorbidities, evolving over distinct time courses. Within a prodromal phase that can extend for one to three decades, opportunities and challenges exist in identifying crucial tipping points in progression and opportunities for prevention.

METHOD: Our study aimed to identify subgroups within the 389 individuals at high-risk for AD (65.6±6.4 years old, 67.1% female, 38.8% APOE ε4 carriers) from the Wisconsin Registry for Alzheimer's Prevention data, 2001-2022. We analyzed prospectively collected data covering patient characteristics (age, sex, race, and APOE ε4 carrier status), medical history (history of diabetes, hypertension, and hyperlipidemia), plasma biomarkers (amyloid-β (Aβ) 40, Aβ42, Aβ40/42 ratio, phosphorylated tau (p-tau) 181, and p-tau 217), and blood laboratory parameters (insulin, glucose, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol). Employing classical clustering methodologies (CCMs, k-means (KMs), KMs with principal component analysis, hierarchical clustering (HC), and HC with dynamic time warping) to inform the unsupervised deep embedded clustering (DEC) algorithm, we evaluated cluster membership and assessed clinical validity. Variable contributions to the predicted cluster membership were assessed using SHapley Additive exPlanations values.

RESULT: Our DEC findings demonstrated promising results by identifying more distinct risk profile patterns for each cluster (n = 6) compared to CCMs (n = 2); achieving a more evenly distributed partitioning of participants into clusters with increased stability, measured by Jaccard and entropy scores; and validating the clinical recognizability based on laboratory values, plasma biomarkers, physician cognitive diagnoses, and Preclinical Alzheimer Cognitive Composite scores. Cluster characterization revealed participants in cluster 6 (n = 44) were most at-risk for AD, consisting of female APOE ε4 carriers with elevated p-tau levels. Conversely, cluster 4 (n = 57) was the least at-risk, youngest cluster, comprising females with fewer comorbid conditions and the lowest AD biomarker levels. Cluster 3 (n = 81) represented the control population.

CONCLUSION: Going forward, these outcomes will enable a robust pipeline for integrating electronic medical record data, empowering diverse patient characterization, and better identify those at risk to implement personalized preventative treatment within heterogeneous populations at risk for AD.},
}

Humans
Female
*Biomarkers/blood
Male
*Alzheimer Disease/blood/genetics/diagnosis
Aged
Amyloid beta-Peptides/blood
tau Proteins/blood
Middle Aged
Apolipoprotein E4/genetics
Registries
Risk Factors

@article {pmid41499862,
year = {2025},
author = {Nadais, A and Castro, C and Martins, I and Trigo, D and Nunes, C and Henriques, AG and de Lourdes Pereira, M and da Cruz E Silva, OAB},
title = {Nanoparticle-mediated Zn delivery impacts neural protein phosphatase activity.},
journal = {Biomaterials advances},
volume = {182},
number = {},
pages = {214675},
doi = {10.1016/j.bioadv.2025.214675},
pmid = {41499862},
issn = {2772-9508},
abstract = {In recent years, the use of nanoparticles (NPs) in diagnosis and treatment of different disorders has been a matter of intensive research. Due to their physical and chemical properties, zinc oxide nanoparticles (ZnO NP) have been explored in a range of biological applications, including cancer and neurological diseases. Regarding the latter, while some studies report protective effects of ZnO NP in cultured cells and animal models, others indicate that these NPs have a harmful impact on the brain, such as promoting oxidative stress and cell death. Previous results from our group have suggested beneficial effects for zinc (Zn) cations in both modulating protein aggregation and on Alzheimer's disease (AD) pathology. In this context, the effect of encapsulated Zn as a nanoparticle on protein aggregation and its influence on protein phosphorylation events associated with AD were explored. The results herein presented show that ZnO NP contributed to a decrease in protein aggregation in neuronal cells. However, these NPs were also found to decrease PP1 and PP2A activity, potentially contributing to increased phosphorylation of tau and APP, which are AD pathology hallmarks. In conclusion, while the use of NPs as a Zn delivery system may offer benefits by reducing aggregate formation, they also appear to induce undesired molecular changes, like those observed in AD. Therefore, a holistic approach should be incorporated as we move forward in this research line, as their effects on distinct cellular processes may be dual edged.},
}

@article {pmid41499797,
year = {2025},
author = {Grigoli, MM and Pachane, BC and Fuzer, AM and de Oliveira, SD and Targas, ABA and Alexandre-Silva, V and Selistre-de-Araujo, HS and Manzine, PR and Cominetti, MR},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105542},
doi = {10.1002/alz70856_105542},
pmid = {41499797},
issn = {1552-5279},
mesh = {Humans ; Tretinoin/pharmacology ; Cell Line, Tumor ; *Cell Differentiation/drug effects/physiology ; Laminin/pharmacology ; Biomarkers/metabolism ; *Neurons/drug effects/metabolism ; Acetylcholinesterase/metabolism ; Neuroblastoma/pathology ; Tubulin/metabolism ; Neurites ; Extracellular Matrix/metabolism ; },
abstract = {BACKGROUND: The SH-SY5Y neuroblastoma cell line is a valuable in vitro model for studying neuronal differentiation and neurodegenerative diseases like Alzheimer's disease (AD). Traditional differentiation protocols mainly use retinoic acid (RA); however, they lack extracellular matrix (ECM) components that are critical for mechanotransduction and cellular adhesion, which limits their physiological relevance. Laminins, a key ECM glycoprotein, play an essential role in neurite outgrowth and synaptic formation, indicating their potential to enhance neuronal differentiation.

METHOD: SH-SY5Y cells were cultured in DMEM/F12 supplemented with fetal bovine serum (FBS) and essential additives. Differentiation was induced using RA (10 µM and 25 µM) and a laminin-rich ECM (LrECM). Plates were pre-coated with Matrigel® (a laminin-rich ECM) before seeding the cells. Differentiation efficiency was monitored over 10 days through light microscopy, immunofluorescence for neuronal markers (NeuN and β3-tubulin), and acetylcholinesterase (AChE) activity assays. Western blotting assessed β3-tubulin expression, and neurite lengths were quantified using FIJI software.

RESULT: The combined RA and LrECM treatment significantly enhanced SH-SY5Y differentiation when compared to RA alone. Neuronal morphology, marked by extensive neurite outgrowth, became evident as early as day 4 and was sustained for up to 10 days. Immunofluorescence confirmed increased NeuN expression, showing a shift from cytoplasmic to perinuclear localization over time. β3-tubulin levels remained consistently high in LrECM-treated cells, unlike those treated with RA alone, which demonstrated a decline after day 7. Enhanced cholinergic differentiation was indicated by elevated AChE activity, particularly at 25 µM RA, although higher RA concentrations were unable to sustain neuronal characteristics and raised concerns about cytotoxicity.

CONCLUSION: The incorporation of LrECM into SH-SY5Y differentiation protocols significantly enhances neuronal differentiation and maintains neuron-like characteristics, providing a more physiologically relevant in vitro model for studying AD and other neurodegenerative diseases. This approach enables cost-effective, rapid differentiation and more accurately mimics the brain microenvironment, establishing a strong platform for neurobiological research and therapeutic screening.},
}

Humans
Tretinoin/pharmacology
Cell Line, Tumor
*Cell Differentiation/drug effects/physiology
Laminin/pharmacology
Biomarkers/metabolism
*Neurons/drug effects/metabolism
Acetylcholinesterase/metabolism
Neuroblastoma/pathology
Tubulin/metabolism
Neurites
Extracellular Matrix/metabolism

@article {pmid41499417,
year = {2025},
author = {Young, AL and Wijeratne, PA and Aksman, LM and Binette, AP and Strandberg, O and Oxtoby, NP and Altmann, A and Alexander, DC and Stomrud, E and Palmqvist, S and Mattsson-Carlgren, N and Vogel, JW and Hansson, O},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104804},
doi = {10.1002/alz70856_104804},
pmid = {41499417},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/metabolism/cerebrospinal fluid ; Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/pathology ; Male ; Female ; *Biomarkers/cerebrospinal fluid/metabolism ; Aged ; Disease Progression ; *Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Sweden ; *Brain/diagnostic imaging/metabolism ; Middle Aged ; *Amyloid/metabolism ; },
abstract = {BACKGROUND: Amyloid and tau accumulation in Alzheimer's disease is known to be dynamic, with expected rates of accumulation varying depending on disease stage. Establishing the precise timeline of amyloid and tau accumulation and quantifying their dynamic progression is important for identifying an optimal intervention window and predicting treatment response.

METHOD: 960 individuals were selected from the Swedish BioFINDER-2 study with at least two tau-PET scans (Table 1; follow-ups were at 1 year (N = 66), 2 years (N = 924), 4 years (N = 335); 6 years (N = 60)). Two intersecting data subsets were selected: 773 individuals having at least two amyloid-PET scans for estimating amyloid duration, and 434 CSF-amyloid-positive individuals for comparison with timelines across the whole population. Regional tau-PET SUVR abnormality was computed in five established data-driven regions using mixture modelling. A novel explicit-duration version of the temporal event-based model (T-EBM) was used to determine the order and timeline of global amyloid-PET and regional tau-PET abnormality. The explicit duration approach accounts for censoring of an individual's first and last visit and handles arbitrary time intervals.

RESULT: The T-EBM inferred that tau accumulates in a Braak-like pattern (Figure 1a), estimating an average timeline of global amyloid and regional tau accumulation (Figure 1b) of around 20 years. Progression from stage 1 (amyloid) to stage 2 (entorhinal tau) was estimated to take 8 years on average, from stage 2 to stage 3 (temporal lobe tau) 5.5 years, and 2-3 years between each subsequent stage. The timeline was consistent in amyloid-positive individuals (most amyloid-negative individuals were stage 0 and did not influence the timeline). Figure 1c shows the number of individuals progressing between stages at follow-up. Individuals who progressed in stage (progressors) were older, had more advanced symptoms (diagnosis), more APOE4 alleles, worse MMSE scores, and were more frequently amyloid-positive compared to non-progressors (Table 2).

CONCLUSION: Amyloid accumulates slowly, after which tau spreads from the entorhinal cortex to the temporal lobe, initially at a slower pace before accelerating to a faster rate across the cortex. This data indicates that slower rates of accumulation would be expected at earlier stages. Work is ongoing validating these timelines in additional datasets.},
}

Humans
*tau Proteins/metabolism/cerebrospinal fluid
Positron-Emission Tomography
*Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/pathology
Male
Female
*Biomarkers/cerebrospinal fluid/metabolism
Aged
Disease Progression
*Amyloid beta-Peptides/metabolism/cerebrospinal fluid
Sweden
*Brain/diagnostic imaging/metabolism
Middle Aged
*Amyloid/metabolism

@article {pmid41499318,
year = {2026},
author = {Melrose, J},
title = {Roles for Electrochemical Proton Gradients in Mitochondrial Energy Production and Neurosensory Processes in Health and Disease.},
journal = {Developmental neurobiology},
volume = {86},
number = {1},
pages = {e70006},
doi = {10.1002/dneu.70006},
pmid = {41499318},
issn = {1932-846X},
support = {//Melrose Personal Research Fund/ ; },
mesh = {Humans ; Animals ; *Mitochondria/metabolism ; *Energy Metabolism/physiology ; *Protons ; *Proton-Motive Force/physiology ; *Nervous System Diseases/metabolism ; Oxidative Stress/physiology ; },
abstract = {This study reviews the roles of proton electrochemical gradients in ubiquitous mitochondrial energy production systems in cellular activation and functions in neurosensory signaling. Proton electrochemical gradients crucially shaped the evolution of life. The emergence of the proton-motive force in mitochondria was fundamental in energy production and central to the function of eukaryotic cells. Dysfunctional mitochondria, however, result in impaired formation of proton gradients and a wide spectrum of diseases. This is particularly prominent in tissues with high energetic demands, such as muscle and nervous tissues. Oxidant stress generated by dysfunctional proton conductance in the brain results in Alzheimer's and Parkinson's disease, muscular sclerosis, amyotrophic sclerosis, and Huntington's disease. In these disorders, oxidative stress, protein misfolding, and neuroinflammation lead to dysfunctional neuronal activity, neuronal damage, and death. Advancements in nanozyme-engineered synthetic enzymes offer a promising innovative approach to the treatment of these disorders. Nanozymes target proton conductance and the oxidant species they generate, scavenging oxygen free radicals and restoring redox balance, and offer neuronal protection and functional recovery of brain tissues. Neural injury and associated neurological diseases affect almost 1 billion people globally, so there is a clear need to develop effective methods that stimulate neural repair and regeneration. Glycosaminoglycans with proton capture and transport properties regulate intercellular signaling processes, synaptic functions, and cellular communication. Electroconductive hydrogels are showing impressive results in neural repair and regeneration. Glycosaminoglycans, particularly keratan sulfate, show useful electroconductive proton capture and transport properties, suggesting they may be worth evaluation in such procedures.},
}

Humans
Animals
*Mitochondria/metabolism
*Energy Metabolism/physiology
*Protons
*Proton-Motive Force/physiology
*Nervous System Diseases/metabolism
Oxidative Stress/physiology

@article {pmid41499301,
year = {2026},
author = {Mohasel-Roodi, M and Nozari, M and Shamsara, A and Basiri, M and Mirzaie, V and Baghalishahi, M},
title = {Effects of Dexmedetomidine on the Behavioral Outcomes in Streptozotocin-Induced Alzheimer's Disease Rats.},
journal = {Brain and behavior},
volume = {16},
number = {1},
pages = {e71196},
doi = {10.1002/brb3.71196},
pmid = {41499301},
issn = {2162-3279},
support = {402000357//Kerman Neuroscience Research Center, Kerman University of Medical Sciences/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced ; *Dexmedetomidine/pharmacology/administration & dosage ; Streptozocin/pharmacology ; Rats, Wistar ; Male ; Rats ; *Behavior, Animal/drug effects ; Anxiety/drug therapy ; Maze Learning/drug effects ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; *Adrenergic alpha-2 Receptor Agonists/pharmacology ; Cognitive Dysfunction/drug therapy ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive and prevalent neurodegenerative disorder characterized by progressive cognitive decline and memory impairment. Intracerebroventricular (ICV) administration of streptozotocin (STZ) in rodents recapitulates key features of sporadic AD, including brain insulin resistance and oxidative stress. Dexmedetomidine (Dex), a highly selective α2-adrenergic receptor agonist, has demonstrated neuroprotective and anti-inflammatory properties, suggesting its potential utility as a therapeutic approach for AD.

METHODS: Seventy adult male Wistar rats were randomly allocated to seven experimental groups: Control, Sham, STZ, Sham + Dex (25 µg/kg), and STZ + Dex (25, 50, 100 µg/kg). Cognitive performance and anxiety-like behaviors were evaluated using the open-field test (OFT), elevated plus maze (EPM), Y-maze test, and Morris water maze (MWM).

RESULTS: In the Y-maze, STZ-treated rats exhibited significant reductions in spontaneous alternation behavior (p = 0.002), which were significantly reversed by Dex (25 µg/kg, p = 0.002). In the MWM, the STZ administration resulted in prolonged escape latencies and increased path lengths compared with Control animals (p < 0.05). Treatment with Dex (25 µg/kg) significantly improved spatial learning and memory retention (p < 0.05). No significant differences were observed in locomotor activity and anxiety-related behaviors in the OFT or EPM.

CONCLUSIONS: These findings indicate that Dex at 25 µg/kg attenuates STZ-induced cognitive deficits, likely through neuroprotective and anti-inflammatory mechanisms. The results highlight Dex as a promising candidate for AD therapy, though further research is required to elucidate its underlying molecular pathways. The study supports the potential repurposing of Dex for neurodegenerative disorders.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced
*Dexmedetomidine/pharmacology/administration & dosage
Streptozocin/pharmacology
Rats, Wistar
Male
Rats
*Behavior, Animal/drug effects
Anxiety/drug therapy
Maze Learning/drug effects
Disease Models, Animal
Neuroprotective Agents/pharmacology
*Adrenergic alpha-2 Receptor Agonists/pharmacology
Cognitive Dysfunction/drug therapy

@article {pmid41498900,
year = {2026},
author = {Lin, ZY and Cai, LL and Lin, JX and Zheng, GY},
title = {Tiaobu Xinshen Recipe Improves Cognitive Deficits by Alleviating Synaptic Ultrastructure Degradation and Reducing Amyloid β in Transgenic Mice of Alzheimer's Disease.},
journal = {Chinese journal of integrative medicine},
volume = {},
number = {},
pages = {},
pmid = {41498900},
issn = {1993-0402},
abstract = {OBJECTIVE: To investigate the effect of Tiaobu Xinshen Recipe (TXR) on cognitive function of 5xFAD transgenic mice and explore the potential mechanisms.

METHODS: Six-month-old male wild-type (WT) mice and 5xFAD transgenic mice were randomly divided into vehicle (0.9% NaCl), TXR (granules, 4.18 g/kg) and donepezil (0.625 mg/kg) groups using a random number table, respectively, which were given intragastric administration once a day for 60 d. Spatial learning and memory performance was tested with modified Morris water maze (MMWM) test. Synaptic ultrastructure in the hippocampal CA1 region was observed by transmission electron microscopy. The levels of amyloid β (Aβ), the major amyloid precursor protein (APP)-cleaving enzymes and Aβ-degrading enzymes including β-secretase, α-secretase, neprilysin (NEP) and insulin-degrading enzyme (IDE), were detected by immunohistochemistry staining and Western blot, respectively.

RESULTS: In MMWM test, when compared with the 5xFAD-vehicle group, 5xFAD-TXR group demonstrated a significantly shorter escape latency to the platform and increased number of platform crossings and time spent in target quadrant (P<0.05 or P<0.01). The ultrastructure of synapse in the hippocampal CA1 region of mice in the 5xFAD-TXR group was significantly changed, including increased numbers of mitochondria and synaptic vesicles, intact synaptic membrane, and thickened postsynaptic density. The Aβ load was markedly decreased in the cerebral cortex and hippocampus CA1 subregion of TXR-treated 5xFAD mice (P<0.05). TXR treatment decreased APP levels and increased IDE expression in brains of 5xFAD mice (P<0.01). However, TXR treatment had no effect on α- and β-secretase, and NEP in 5xFAD mice (P>0.05).

CONCLUSION: TXR improves cognitive dysfunction in 5xFAD mice by alleviating synaptic ultrastructure degradation and reducing Aβ.},
}

@article {pmid41498751,
year = {2025},
author = {Biel, D and Steward, A and Dewenter, A and Dehsarvi, A and Zhu, Z and Roemer-Cassiano, S and Frontzkowski, L and Hirsch, F and Brendel, M and Franzmeier, N},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104771},
doi = {10.1002/alz70856_104771},
pmid = {41498751},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; *tau Proteins/blood ; Aged ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Longitudinal Studies ; *Cognitive Dysfunction/diagnostic imaging ; Amyloid beta-Peptides ; Aged, 80 and over ; Brain/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: With the approval of anti-amyloid therapies in Alzheimer's disease (AD), surrogate biomarkers are urgently needed to monitor treatment effects that translate into clinical benefits. Candidate biomarkers, including amyloid-PET, tau-PET, plasma phosphorylated tau (p-tau), and MRI-assessed atrophy, capture core pathophysiological changes in AD. While cross-sectional biomarker assessments are critical for diagnosis and staging, biomarker change rates may better reflect disease dynamics, making them more suitable for monitoring treatment efficacy. Therefore, we determined which biomarker most effectively tracks cognitive changes in AD, identifying those best suited for efficient monitoring of disease-modifying treatments.

METHOD: We leveraged ADNI (N = 108) and A4 (N = 151) participants with longitudinal AD biomarker data (global amyloid-PET, temporal meta tau-PET, plasma p-tau217, MRI-assessed cortical thickness in the AD signature region) together with cognitive assessments (ADNI: MMSE, ADAS13, CDR-SB; A4: MMSE, PACC). Linear mixed models were used to calculate change rates for biomarkers and cognition. To test whether biomarker changes track cognitive decline, linear models were applied, to test biomarker change rates as a predictor of cognitive change rates. Standardized beta values from bootstrapped linear models were extracted to compare the strengths of correlations between biomarkers and cognitive decline. For non-parametric comparisons, 95% confidence intervals (CIs) of standardized beta values were compared. Models were controlled for age, sex, education, and baseline cognition, with ADNI models additionally adjusted for clinical status.

RESULT: In both cohorts, changes in temporal tau-PET, plasma p-tau217, and MRI-assessed cortical thickness were associated with cognitive decline (ADNI: Figure 1; A4: Figure 2). Amyloid-PET changes showed no significant association with cognitive changes (ADNI: Figure 1A+F+K; A4: Figure 2A+F). Bootstrapping confirmed that tau-PET, plasma p-tau217, and cortical thickness track cognitive decline, but not amyloid-PET (ADNI: Figure 1E+J+O; A4: Figure 2E+J). Overlapping CIs for tau-PET and plasma p-tau217 indicated comparable predictive accuracy.

CONCLUSION: Our findings demonstrate that tau-PET and plasma p-tau217 are robust biomarkers for monitoring cognitive changes, with plasma p-tau217 offering a cost-effective, scalable alternative for clinical use. Changes in amyloid-PET do not reliably reflect cognitive decline, limiting its utility as a treatment monitoring tool. Although cortical thickness correlates with cognitive changes, its application is limited by pseudoatrophy and volume loss induced by anti-amyloid antibody treatments.},
}

Humans
*Biomarkers/blood
Male
Female
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
*tau Proteins/blood
Aged
Magnetic Resonance Imaging
Positron-Emission Tomography
Longitudinal Studies
*Cognitive Dysfunction/diagnostic imaging
Amyloid beta-Peptides
Aged, 80 and over
Brain/pathology/diagnostic imaging

@article {pmid41498704,
year = {2025},
author = {Bathe, T and Salomasova, S and Lalia, M and Kunze, LH and Palumbo, G and Oos, R and Joseph, E and Brendel, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104796},
doi = {10.1002/alz70856_104796},
pmid = {41498704},
issn = {1552-5279},
mesh = {Animals ; *Biomarkers/cerebrospinal fluid/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Alzheimer Disease/drug therapy ; Positron-Emission Tomography ; tau Proteins/metabolism ; Humans ; Brain/metabolism/pathology/diagnostic imaging/drug effects ; *Tauopathies/drug therapy ; Microglia/metabolism ; },
abstract = {BACKGROUND: The prevalence of neurodegenerative diseases (ND), including Alzheimer's disease (AD) and non-AD tauopathies, is projected to rise significantly by 2050 due to an aging global population. Chronic neuroinflammation, driven by glial activation in response to protein pathologies, is a major contributor to disease progression. Targeting glial dysfunction through immunomodulatory therapies offers a promising approach to mitigate the effects of tauopathies and other ND.

METHOD: PS19 mice receive chronic treatment with GV1001 over 5 months. Serial neuroimaging techniques, including PET scans targeting tau protein, microglial activation, and astrocytic responses, are employed to assess treatment effects in vivo (Figure 1). Postmortem validation is performed using immunohistochemistry and biochemical methods, comparing treated mice to placebo and non-transgenic controls.

RESULT: The research scope is to monitor the efficacy of GV1001 in a transgenic tau mouse model (PS19) with an early-intervention biomarker study using molecular biology and neuroimaging techniques including TSPO (microglia) PET, deprenyl (astroglia) PET, tau PET (perfusion and retention) and CSF markers of inflammation (e.g. sTREM2) and neurodegeneration (NfL). Preliminary findings, expected to be presented at the conference, will provide insights into the drug's ability to modulate glial activity, restore homeostasis, and reduce tau pathology.

CONCLUSION: This study highlights the potential of monitoring immunomodulatory strategies to address the complex interplay between chronic neuroinflammation and protein aggregation in ND. If successful, these findings could inform the development of novel therapeutic approaches for AD and related disorders, bridging the gap between preclinical research and clinical application.},
}

Animals
*Biomarkers/cerebrospinal fluid/metabolism
Mice
Mice, Transgenic
Disease Models, Animal
*Alzheimer Disease/drug therapy
Positron-Emission Tomography
tau Proteins/metabolism
Humans
Brain/metabolism/pathology/diagnostic imaging/drug effects
*Tauopathies/drug therapy
Microglia/metabolism

@article {pmid41498508,
year = {2025},
author = {Doecke, JD and Chenna, A and Lo, M and Badal, Y and Yee, B and Martone, RL and Petropoulos, C and Fowler, CJ and Laws, SM and Rainey-Smith, SR and Martins, RN and Rowe, CC and Masters, CL and Winslow, JW},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104702},
doi = {10.1002/alz70856_104702},
pmid = {41498508},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Amyloid beta-Peptides/blood/metabolism ; Male ; Female ; *Cognitive Dysfunction/blood/diagnostic imaging/diagnosis ; Aged ; *Alzheimer Disease/blood/diagnostic imaging/diagnosis ; *tau Proteins/blood ; Peptide Fragments/blood ; Cohort Studies ; Positron-Emission Tomography ; Aged, 80 and over ; Australia ; Middle Aged ; },
abstract = {BACKGROUND: With the increasing number of countries approving disease-modifying therapies (DMTs) for patients with either Mild Cognitive Impairment (MCI) or mild Alzheimer's disease (AD), it is vitally important to streamline treatment assessment processes. Blood-based biomarkers (BBMs) have been suggested as rivals to cerebrospinal fluid (CSF) biomarkers in their accuracy to detect neocortical Amyloid-Beta (Aβ). However, there is little consensus on potential thresholds and resulting confirmatory test performance for international use in target populations.

METHOD: Two separate sub-cohorts-the AD continuum cohort (ADCC) [cognitively impaired + unimpaired; N = 197] and the intention to treat cohort (ITTC) [cognitively impaired; N = 200]-from the Australian Imaging Biomarkers and Lifestyle (AIBL) study of aging, were designed to test the accuracy and potential cut-offs of leading BBM Lumipulse assays from Fujirebio (pTau217 and Aβ42/40) to detect PET-Aβ (centiloid ≥25; amyloid prevalence ∼63%).

RESULT: Using the pTau217/Aβ42 ratio significantly improved the area under the curve (AUC) over pTau217 alone to detect PET-Aβ positivity in both the ADCC and ITTC (Figure 1A, ADCC p = 0.01; Figure 1B: ITTC p = 0.009). The Youden's Index cut-off for pTau217 was higher in the ITTC compared to the ADCC (0.25 pg/mL vs. 0.179 pg/mL). The highest accuracy observed for either single BBMs, the ratio of BBMs, or the linear combination of BBMs that included age, gender, and APOE ε4 was 93-95% in the ADCC (linear combination of pTau217, Aβ42/40, age, gender, and APOE ε4; pTau217/Aβ42 ratio) and 95-97% in the ITTC (linear combination; pTau217/Aβ42 ratio). The lowest number of participants in the intermediate zone using dual cut-offs at 95% sensitivity and specificity was 9% and 14% for the pTau217/Aβ42 ratio in the ADCC and ITTC (92-93% accuracy), and 0% for the linear combination (pTau217, Aβ42/40, age, gender, and APOE ε4) in the ITTC (95% accuracy).

CONCLUSION: The general performance of the Lumipulse assays was similar across both the ADCC and ITTC, indicating strong repeatability independent of clinical stage. Focusing on only participants eligible for DMTs increased sensitivity and improved accuracy for the Aβ-containing pTau217/Aβ42 ratio and linear combination of markers, and resulted in small numbers of unclassified participants by the test.},
}

Humans
*Biomarkers/blood
*Amyloid beta-Peptides/blood/metabolism
Male
Female
*Cognitive Dysfunction/blood/diagnostic imaging/diagnosis
Aged
*Alzheimer Disease/blood/diagnostic imaging/diagnosis
*tau Proteins/blood
Peptide Fragments/blood
Cohort Studies
Positron-Emission Tomography
Aged, 80 and over
Australia
Middle Aged

@article {pmid41498480,
year = {2026},
author = {Goodall, LS and Lennon, MJ and Sachdev, PS and Gorelick, PB and Kovacic, JC and Samaras, K},
title = {Current and Emerging Therapeutic Approaches for Vascular Cognitive Impairment and Dementia.},
journal = {Journal of the American College of Cardiology},
volume = {87},
number = {1},
pages = {77-100},
doi = {10.1016/j.jacc.2025.09.1502},
pmid = {41498480},
issn = {1558-3597},
mesh = {Humans ; *Dementia, Vascular/therapy/prevention & control ; *Cognitive Dysfunction/therapy ; },
abstract = {Cardiovascular risk factors contribute to the majority of dementia cases, with about 20% directly attributable to vascular cognitive impairment and dementia (VCID). VCID treatment developments have been slow compared with Alzheimer's disease (AD), which now has several FDA-approved symptom- and disease-modifying agents. In the second part of this JACC Seminar Series, advances and new perspectives on the management and prevention of VCID are reviewed. There is reasonable evidence that cognitive enhancers (donepezil, galantamine, and memantine) modestly improve cognition in vascular dementia (VaD), the most severe form of VCID, especially if there is associated AD pathology. Antidepressants may benefit those with depression and stroke, but they have poor efficacy in those with depression and VaD alone. Behavioral, social, and environmental interventions are first-line therapies for managing VCID-associated agitation and psychosis. Second-line antipsychotics have not been trialed in those with VaD alone, but are beneficial where AD and VaD co-exist, with risperidone and quetiapine effective in reducing psychosis and agitation. Primary prevention of VCID includes identifying and managing cardiometabolic risk factors along with manifestations of covert cerebrovascular disease. Both primary and secondary VCID prevention involve management of cardiovascular risks, specifically hypertension, diabetes mellitus, smoking, atrial fibrillation, obesity, and sedentariness. Management of vascular risk factors may moderately reduce the risk of incident cognitive impairment. Novel interventions currently being evaluated in clinical trials are discussed. The discovery and utilization of VCID and AD biomarkers will enhance the specificity and effectiveness of interventions such that a precision-medicine approach to disease-specific medical therapy may be taken.},
}

Humans
*Dementia, Vascular/therapy/prevention & control
*Cognitive Dysfunction/therapy

@article {pmid41498479,
year = {2026},
author = {Sachdev, PS and Bentvelzen, AC and Gustafson, D and Hansra, GK and Hosoki, S and Jiang, J and Lennon, MJ and Moro, MA and Saks, DG and Samaras, K and Kovacic, JC and Kalaria, R},
title = {Vascular Cognitive Impairment and Dementia: Clinical Features, Neuropathology, and Biomarkers.},
journal = {Journal of the American College of Cardiology},
volume = {87},
number = {1},
pages = {52-76},
doi = {10.1016/j.jacc.2025.11.008},
pmid = {41498479},
issn = {1558-3597},
mesh = {Humans ; Biomarkers/metabolism ; *Dementia, Vascular/diagnosis/pathology ; *Cognitive Dysfunction/diagnosis/etiology ; Risk Factors ; *Brain/pathology ; },
abstract = {Vascular cognitive impairment and dementia (VCID), ie, cognitive impairment secondary to cerebrovascular disease (CeVD), is the second most common form of dementia after Alzheimer's disease (AD), accounting for 15% to 20% of all cases. CeVD, in fact, contributes to dementia alongside other neuropathologies in up to 75% of dementia cases. CeVD and AD not only frequently co-occur in the brain, but they may also interact, and some VCID risk factors (midlife hypertension and diabetes) also increase AD risk. Because CeVD and cardiovascular disease share risk factors and pathophysiology, the cardiovascular clinician is likely to encounter both in the clinic. Moreover, common cardiac disorders, such as atrial fibrillation, heart failure, acute coronary syndrome, and valvular disease, increase VCID risk. There have been recent developments in the diagnostic criteria for VCID, with advances in risk biomarkers, treatment, and prevention of cognitive impairment and dementia. The diagnosis of VCID is a 2-step process, with the initial identification of a cognitive syndrome followed by the establishment of a predominantly vascular etiology, guided by clinical history and examination and substantiated by neuroimaging, preferably magnetic resonance imaging. Clinical presentations include an acute onset, a stepwise decline, a fluctuating course if caused by multiple strokes, or a gradual slow progression if attributable to cerebral small vessel disease. Cognitive deficits can be found in several domains, such as information-processing speed, attention, executive function, and emotional lability, sometimes referred to as the subcortical syndrome, often seen in the early stages of VCID without cortical infarcts. The diagnosis is supported by the identification of large and small infarcts, lacunes, white matter hyperintensities, dilated perivascular spaces and cerebral microbleeds using magnetic resonance imaging. This part 1 of a 2-part JACC review series describes the clinical features, pathophysiology, and biomarkers of VCID for cardiovascular clinicians who have a critical role in its early identification, management, and prevention in their patients.},
}

Humans
Biomarkers/metabolism
*Dementia, Vascular/diagnosis/pathology
*Cognitive Dysfunction/diagnosis/etiology
Risk Factors
*Brain/pathology

@article {pmid41498388,
year = {2025},
author = {Chiotis, K and Blazhenets, G and Eloyan, A and Maiti, P and Zhang, J and Touroutoglou, A and Kirby, K and Hammers, DB and Carrillo, MC and Dickerson, BC and Apostolova, LG and Rabinovici, GD and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104661},
doi = {10.1002/alz70856_104661},
pmid = {41498388},
issn = {1552-5279},
mesh = {Humans ; Male ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; Female ; *tau Proteins/metabolism ; Biomarkers/metabolism ; *Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Longitudinal Studies ; Aged ; Cognitive Dysfunction/drug therapy/diagnostic imaging ; Middle Aged ; Brain/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: In clinical trials, monoclonal antibodies targeting Aβ pathology have shown strong target engagement, resulting in rapid Aβ clearance and a deceleration in rate of clinical decline. Now that these treatments are approved and implemented in clinical practice, we could assess their effects in observational studies involving these patients.

METHOD: We analyzed data from 20 participants with early-onset Alzheimer's disease (EOAD) in the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort, treated with Aducanumab (n = 4), Lecanemab (n = 15), or both (one transitioning from Aducanumab to Lecanemab). All participants had MCI or mild dementia at baseline, longitudinal Aβ and tau PET, as well as cognitive assessments, with at least one observation before and after treatment initiation. We applied piecewise regression with a knot at the treatment start, to evaluate changes in Aβ and tau PET burden and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. We compared the trajectories of treated participants with an untreated group (i.e., treated-untreated comparison) from LEADS, matched for age, sex, APOE ε4 genotype, pretreatment Aβ and tau PET load, CDR-SB, and follow-up duration, using a 1:3 matching design.

RESULT: The median treatment duration was 8 months (IQR=5-10). In the piecewise regression model, the treated group showed significant decreases in Aβ burden post-treatment (Δ=-52 Centiloids/yr, p <0.001) with widespread neocortical involvement (Figure 1). However, no significant inflection in tau burden (Δ=0 SUVR/yr, p = 0.58) or CDR-SB (Δ=0.3 units/yr, p = 0.57) trajectories was observed. In the treated-untreated comparison, the treated group showed a trend toward slower increases in CDR-SB scores post-treatment (ΔT=-1.8, p = 0.07) compared to the untreated group (Figure 2). Aβ levels significantly decreased in the treated group compared to the untreated group (ΔΤ=-8.5, p <0.001). No significant differences in tau trajectories were observed between groups (ΔT=0.4, p = 0.68), with both showing increases in cortical regions of interest.

CONCLUSION: We observed excellent target engagement, with piecewise regression models showing rates of Aβ clearance comparable to those seen in Phase 3 trials. The study was underpowered to detect cognitive benefits, which are limited over a short follow-up interval. These findings underscore the utility of observational studies with biomarker data in evaluating treatment efficacy, offering insights that complement traditional randomized trials.},
}

Humans
Male
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
Female
*tau Proteins/metabolism
Biomarkers/metabolism
*Amyloid beta-Peptides/metabolism
Positron-Emission Tomography
*Antibodies, Monoclonal, Humanized/therapeutic use
Longitudinal Studies
Aged
Cognitive Dysfunction/drug therapy/diagnostic imaging
Middle Aged
Brain/diagnostic imaging/metabolism

@article {pmid41496378,
year = {2025},
author = {Zhao, Y and Lu, H and Jiang, X},
title = {Advance in neuroprotective effects of proanthocyanidins (PCs): Structure, absorption, bioactivities, mechanism, and perspectives.},
journal = {Pharmacological research},
volume = {223},
number = {},
pages = {108082},
doi = {10.1016/j.phrs.2025.108082},
pmid = {41496378},
issn = {1096-1186},
abstract = {With the global population growing and aging, along with increasing environmental, metabolic, and lifestyle-related risk factors, the worldwide incidence of stroke, Alzheimer's disease (AD) and other dementias, meningitis, and other neurological disorders-along with associated mortality-has risen significantly. Proanthocyanidins (PCs), which are oligomers and polymers of flavan-3-ols, are widely distributed across the plant kingdom, including in grape seeds, cinnamon, apples, cranberries, lotus seeds, and pine bark. They represent the second most abundant class of polyphenols in nature, after lignin. A substantial body of preclinical evidence indicates that PCs exert significant neuroprotective effects through multiple mechanisms. This review provides a systematic overview of the sources, structural characteristics, and bioavailability of PCs, with a focus on their pharmacological mechanisms in nervous system disease. Specifically, it examines their roles in regulating oxidative stress, neuroinflammation, protein homeostasis, apoptosis, autophagy, and key signaling pathways, including Nrf2/HO-1, CREB/BDNF, PI3K/Akt, MAPK, and NF-κB. Furthermore, this review systematically summarized the distinct structural forms of PCs, including monomers, dimers, trimers, and polymers, and explores their structure-activity relationships (SARs) in modulating the gut-brain axis. Additionally, recent advances in PCS-based nano-delivery systems and clinical studies related to neurological disorders are summarized. Growing evidence indicates that microbial metabolism in the gut serves as a key mechanism underlying their neuroprotective effects. Finally, the potential applications of PCs as promising dietary supplements or therapeutic agents for the prevention and treatment of nervous system diseases are discussed, along with existing challenges and future perspectives.},
}

@article {pmid41496364,
year = {2026},
author = {Facchinetti, R and Valenza, M and Ciarla, C and Steardo, L and Serviddio, G and Palombelli, G and Verkhratsky, A and Steardo, L and Canese, R and Cassano, T and Scuderi, C},
title = {Ultramicronized palmitoylethanolamide restores astrocyte-neuron metabolic coupling and Klotho/FGF21 signaling in a triple-transgenic mouse model of Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {118965},
doi = {10.1016/j.biopha.2025.118965},
pmid = {41496364},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD), a multifactorial neurodegenerative disorder, is characterized by metabolic deficiency, neuroinflammation, and synaptic impairment. Astrocyte-neuron metabolic coupling regulates cerebral energy homeostasis through key metabolites such as lactate, glutamate, and taurine. We investigated the therapeutic potential of ultramicronized-palmitoylethanolamide (um-PEA) in restoring the homeostasis of these metabolites in the triple transgenic (3 ×Tg-AD) mouse model of AD. Using in vivo magnetic resonance imaging and spectroscopy (MRI/MRS) combined with Western blot, we evaluated the effects of chronic um-PEA treatment on lactate-glutamate dynamics and taurine metabolism in the frontal cortex and hippocampus of 6- and 12 month-old mice. Our findings demonstrate that 3 ×Tg-AD mice exhibit lactate accumulation, glutamine/glutamate imbalance, and taurine depletion, alongside reduced expression of metabolic processes regulators such as FGF21, Klotho, and insulin receptor. Treatment with um-PEA successfully restored these metabolic changes by: (i) rebalancing lactate-glutamate metabolism, (ii) increasing taurine synthesis and transport, (iii) upregulating FGF21, Klotho, and insulin receptor expression, and (iv) modulating the metalloproteases ADAM10 and ADAM17, which regulate Klotho processing. These results identify um-PEA as a promising metabolic modulator capable of mitigating AD-related neurodegenerative processes. By targeting astrocyte-neuron metabolism and enhancing both FGF21 and Klotho pathways, um-PEA holds significant potential as an adjunctive therapeutic strategy for AD.},
}

@article {pmid41496361,
year = {2026},
author = {Huzián, O and Nagy, LI and Hackler, L and Knapp, L and Kocsis, ÁK and Szöts, I and Tamás, G and Puskás, LG and Molnár, G},
title = {Novel drug candidate binds to delta subunit containing GABAA receptors and improves spatial memory.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {118970},
doi = {10.1016/j.biopha.2026.118970},
pmid = {41496361},
issn = {1950-6007},
abstract = {The hydroxyquinoline derivative Q134R is a promising drug candidate for the treatment of Alzheimer's disease with cytoprotective and cognition-enhancing properties. Radioligand binding assays showed that Q134R reduced [[35]S]TBPS binding, consistent with modulation of the picrotoxin site or conformational states that regulate TBPS accessibility. Electrophysiological recordings in mouse brain slices revealed that Q134R significantly increased tonic inhibitory currents in cortical neurogliaform and dentate gyrus granule cells, both known to express delta subunit-containing GABAA receptors. This effect was abolished in mice deficient in the GABAA delta subunit confirming the delta subunit dependency of Q134R's action. Furthermore, in a scopolamine-induced amnesia model, Q134R treatment significantly improved spatial memory performance in wild-type mice, but not in mice lacking in the delta subunit. These results suggest that Q134R enhances tonic inhibition through delta subunit-containing GABAA receptors, which may contribute to the modulation of memory processes and serve as a protective mechanism in early-stage neurodegenerations. These receptor-mediated effects likely contribute to its broader therapeutic efficacy and may complement its previously reported interactions with signaling pathways such as NFAT and HIF-1.},
}

@article {pmid40511807,
year = {2025},
author = {Dodiya, R and Sharma, P and Israni, D and Kamal, MA and Greig, NH},
title = {Zebrafish-Based Parkinson's Disease Models: Unveiling Genetic Mechanisms and Therapeutic Pathways.},
journal = {CNS & neurological disorders drug targets},
volume = {24},
number = {12},
pages = {900-920},
pmid = {40511807},
issn = {1996-3181},
support = {AG000311//NHG: Intramural Research Program, National Institute on Aging, NIH, USA/ ; },
mesh = {Animals ; *Zebrafish/genetics ; *Parkinson Disease/genetics/therapy ; *Disease Models, Animal ; Humans ; },
abstract = {The zebrafish (Danio rerio) is widely utilised as a live vertebrate model in research on neurological development and nervous system diseases. This species exhibits various distinctive attributes that render it well-suited for investigating neurological disorders such as Parkinson's disease (PD). Zebrafish and humans have a genetic similarity of around 70%, and approximately 84% of the genes associated with human diseases have zebrafish equivalents. The genetic similarities and presence of neurotransmitters like dopamine allow scientists to study PD genes and proteins. Zebrafish are often challenged with neurotoxins to induce Parkinsonian symptoms, allowing researchers to evaluate attendant biochemical pathways. Zebrafish can also repair damaged organs, increasing their potential value in PD research. Because of their regenerative capacity and genetic resemblance to humans, these species can be used to study dopamine neurodegeneration and prospective PD treatments. In addition to PD, zebrafish are helpful models for studying Huntington's disease, Alzheimer's disease, epilepsy, depression, schizophrenia, and anxiety disorders. This article emphasizes significant findings of relevance to PD using the zebrafish model, describing its challenges and benefits. The investigation of key genes, protein pathways, and neurotoxins provides the opportunity to facilitate understanding of the role of dopamine neurotransmitters in PD and expedite the development of potentially promising therapeutic strategies.},
}

Animals
*Zebrafish/genetics
*Parkinson Disease/genetics/therapy
*Disease Models, Animal
Humans

@article {pmid41495612,
year = {2025},
author = {Yang, G and Zhu, D and Zhang, K},
title = {Nose-brain axis: A bridge from the nasal cavity to the central nervous system.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01770},
pmid = {41495612},
issn = {1673-5374},
abstract = {The nose-brain axis is a direct pathway linking the nasal cavity to the central nervous system. Odors, as well as exogenous substances such as pathogens, inflammatory mediators, and drugs, can enter the cranial cavity through pathways including the olfactory nerve, trigeminal nerve, and humoral routes, thereby enabling signal transmission and material exchange from the peripheral nasal cavity to the central nervous system. In recent years, advances in multimodal visualization technologies have made it possible to dynamically monitor the nose-brain axis from the molecular level to the tissue level, providing important means for revealing its functional characteristics and pathological changes. Owing to the existence of the nose-brain axis, nasal inflammation can, through neuro-immune interactions, activate central microglia and astrocytes and induce neuroinflammation, thus promoting the onset and progression of central nervous system diseases. In addition, the nose-brain axis offers a unique route for the treatment of central nervous system disorders. Intranasal drug delivery can bypass the blood-brain barrier, act directly on the central nervous system, increase intracranial drug bioavailability, and produce rapid effects, providing new ideas for treating cross-system diseases. This review systematically summarizes the anatomical pathways of the nose-brain axis, visualization monitoring technologies, and mechanisms by which nasal inflammation affects the central nervous system. It also reviews advances in intranasal drug delivery for emotional disorders, migraine, Parkinson's disease, and Alzheimer's disease, aiming to provide new strategies for studying the mechanisms by which nasal inflammation influences the central nervous system and for cross-system targeted therapy.},
}

@article {pmid41495456,
year = {2026},
author = {Chen, Z and Bi, S and Shan, Y and Wang, F and Wang, Y and Qi, Z and Wang, T and Li, X and Li, S and Xiao, H and Wang, S and Cui, B and Qi, Z and Han, Y and Yan, S and Lu, J and , },
title = {MRI-to-PET synthesis via deep learning for amyloid-β quantification in Alzheimer's disease.},
journal = {European radiology},
volume = {},
number = {},
pages = {},
pmid = {41495456},
issn = {1432-1084},
support = {82102010//National Natural Science Foundation of China/ ; 82394434//National Natural Science Foundation of China/ ; },
abstract = {OBJECTIVES: Amyloid-β (Aβ) PET is crucial for diagnosing and monitoring Alzheimer's disease (AD), but its high cost and radiation exposure limit its use. Deep learning techniques make it possible to generate PET from structured MRI data. In this study, we built a deep learning model to generate 3D synthetic Aβ PET images from structural MRI.

MATERIALS AND METHODS: The generative adversarial network with share parameters (ShareGAN) model was trained and tested with 1009 Aβ PET and paired MRI images from the Alzheimer's Disease Neuroimaging Initiative database and three tertiary hospitals in China. The 3D synthetic model operates on the whole volume rather than 2D image slices, realistically reproducing minor discrepancies between neighboring image planes. ShareGAN-based PET images were evaluated using quantitative metrics and visual assessment. Pearson correlation coefficient and Bland-Altman analyses were used to assess the correlation and concordance between synthetic and real PETs.

RESULTS: 3D Synthetic PET images showed high similarity and correlation with real Aβ PET in external testing sets 1 and 2 in terms of structural similarity index measure (0.898, 0.899), peak signal-to-noise ratio (34.690, 34.725), mean absolute error (0.031, 0.031), and standardized uptake value ratio (R = 0.758, 0.828). The diagnostic accuracy of PET positive or negative status in external testing sets 1 and 2 was 88.5% and 89.4%, respectively.

CONCLUSION: MRI-based 3D synthetic Aβ PET images can serve as a safe and cost-effective tool for Aβ status visualization, providing PET-eligible patients with Aβ PET-like imaging analysis to guide subsequent real Aβ PET scans.

KEY POINTS: Question Amyloid-β (Aβ) PET limitations (high cost, radiation, limited access) hinder early Alzheimer's disease (AD) detection. Clinical practice urgently requires a suitable supplementary method for Aβ pathology assessment. Findings AI-synthesized 3D Synthetic Aβ PET from structural MRI demonstrated strong consistency with real PET and effectively triaged high-risk patients for confirmatory scans. Clinical relevance This non-invasive, cost-effective method holds the promise of enabling wider Aβ pathology screening, reduces unnecessary PET scans, and supports early intervention in resource-limited settings, while preserving diagnostic rigor for treatment decisions.},
}

@article {pmid41494605,
year = {2026},
author = {Viqueira, L and Navarro, E and Negredo, P and Bernal, JA and Rodríguez-Franco, MI and ElenaTortosa, and López, MG},
title = {Long-term NRF2-driven microglial repopulation mitigates microgliosis, neuronal loss and cognitive deficits in tauopathy.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106253},
doi = {10.1016/j.bbi.2026.106253},
pmid = {41494605},
issn = {1090-2139},
abstract = {Tauopathies, including Alzheimer's disease, feature chronic microglial reactivity that drives neuroinflammation and disease progression. Pharmacological microglial depletion and subsequent repopulation using colony stimulating factor 1 receptor inhibitors have emerged as a potential therapeutic strategy to reprogram dysfunctional microglia. Despite promising short-term results, the long-term efficacy and pharmacological modulation of repopulated microglia remain poorly understood. Here, we investigated the long-term effects of microglial repopulation alone and in combination with the activation of the cytoprotective nuclear factor erythroid 2 p45-related factor 2 (NRF2) in an in vivo AAV-hTau[P301L] induced model. Integrating different behavioural, immunohistological and transcriptomic analysis, we evaluated cognitive function, tau pathology, neuronal survival and glial reactivity. We found that, whereas microglial repopulation alone did not significantly affect disease progression, NRF2-driven microglial replenishment sustained cognitive function, prevented hippocampal neuronal loss and restored microglial phenotype. Transcriptomic analyses further revealed that the combined treatment modulated tau- associated mitochondrial gene expression changes. These results highlight the importance of shaping the fate of self-renewed microglia and propose NRF2-mediated microglial repopulation as a potential pharmacological strategy for the treatment of tauopathies.},
}

@article {pmid41493713,
year = {2026},
author = {Hoveizi, E and Doraghi, K and Rostami, E},
title = {Fabrication and Characterization of Resveratrol-Loaded Solid Lipid Nanoparticles: Evaluation of Neuroprotective, Neurobehavioral, and Molecular Outcomes.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {346},
pmid = {41493713},
issn = {1559-1182},
support = {SCU.SB1403.12464//Shahid Chamran University of Ahvaz/ ; },
mesh = {*Resveratrol/pharmacology/administration & dosage/chemistry ; Animals ; *Nanoparticles/chemistry/ultrastructure ; *Neuroprotective Agents/pharmacology/administration & dosage/chemistry ; Male ; Rats ; Oxidative Stress/drug effects ; *Lipids/chemistry ; Antioxidants/pharmacology ; Neural Stem Cells/drug effects/metabolism ; *Behavior, Animal/drug effects ; Rats, Sprague-Dawley ; Interleukin-1beta/metabolism ; Memory/drug effects ; },
abstract = {Neurodegenerative processes involve oxidative stress, inflammation, and disrupted signaling, which contribute to cognitive decline. Resveratrol offers neuroprotection but suffers from poor solubility and bioavailability. Solid lipid nanoparticles (SLNs) can improve solubility, stability, and neural targeting, thereby enhancing efficacy. This study investigates whether SLN/resveratrol treatment modulates neuroprotective targets (HSP70, IL-1β) and antioxidant enzymes (CAT, GPX, SOD) in vitro and whether it improves inactive avoidance memory in an animal model. SLNs were produced by melting tripalmitin and palmitic acid, adding resveratrol, Tween, and butanol, then combining with water and stirring for 1 day. The resulting formulations were characterized using FTIR, electron microscopy, and DLS. Neural stem cells (NSCs) were treated with SLNs, resveratrol, and SLN/resveratrol, and the expression of oxidative stress enzymes, HSP70, and IL-1β was analyzed. In vivo, a passive avoidance memory model was induced in rats via electrical destruction of the nucleus basalis of Meynert. Molecular analysis showed that resveratrol increased HSP70 expression by 3.1-fold and significantly decreased IL-1β levels. SLN treatment had no notable effect on these genes, but the SLN/resveratrol increased HSP70 expression by fourfold and significantly reduced IL-1β. Resveratrol significantly upregulated the antioxidant enzymes CAT and GPX, whereas SLNs alone had no effect. The SLN/resveratrol also markedly enhanced CAT and GPX levels. Behavioral tests demonstrated that the SLN/resveratrol treatment improved passive avoidance memory in the Alzheimer's model. Collectively, these results indicate that SLN/resveratrol robustly enhances neuroprotection by modulating signaling pathways, reducing oxidative stress, and improving memory, with the SLN delivery system potentially increasing bioavailability and neural exposure.},
}

*Resveratrol/pharmacology/administration & dosage/chemistry
Animals
*Nanoparticles/chemistry/ultrastructure
*Neuroprotective Agents/pharmacology/administration & dosage/chemistry
Male
Rats
Oxidative Stress/drug effects
*Lipids/chemistry
Antioxidants/pharmacology
Neural Stem Cells/drug effects/metabolism
*Behavior, Animal/drug effects
Rats, Sprague-Dawley
Interleukin-1beta/metabolism
Memory/drug effects

@article {pmid41493675,
year = {2026},
author = {Usman, AS and Manoharan, SD and Che Mohd Nassir, CMN and Abdul Hamid, H and Hein, ZM and Norazit, A and Murthy, J and Zainol, M and Kamaruzzaman, MA and Chiroma, SM and Mustapha, M and Mohd Moklas, MA and Mehat, MZ},
title = {Neuroprotective Effects of Ficus deltoidea in Alzheimer's Disease-Like Rat Model: Insights from Behavior, Histology, and Amyloid Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {345},
pmid = {41493675},
issn = {1559-1182},
support = {(FRGS/1/2021/SKK0/UPM/02/15)//the Ministry of Higher Education under the Fundamental Research Grant Scheme/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism ; *Ficus/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Rats, Wistar ; Disease Models, Animal ; *Plant Extracts/pharmacology/therapeutic use ; Plaque, Amyloid/pathology/drug therapy ; Amyloid beta-Peptides/metabolism ; Hippocampus/pathology/drug effects/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Maze Learning/drug effects ; Rats ; *Behavior, Animal/drug effects ; Spatial Memory/drug effects ; Aspartic Acid Endopeptidases/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and accumulation of amyloid-β (Aβ) plaques. While current treatments offer limited efficacy, medicinal plants such as Ficus deltoidea (FD), a traditional remedy, have shown promise due to their neuroprotective and anti-inflammatory properties. An AD-like phenotype was induced in male Wistar rats using D-galactose and aluminum chloride over 70 days. FD extract was administered orally at 50, 100, and 200 mg/kg. Spatial memory was evaluated using the T-maze test. Histological analyses of the hippocampi's Cornu Ammonis 1 and 3 (CA1 and CA3) regions were conducted via hematoxylin and eosin (H&E) staining, and Aβ plaques deposition was assessed with Congo red. Enzyme-linked immunosorbent assay (ELISA) was used to quantify hippocampal levels of Aβ (1-42) and β-secretase-1 (BACE-1). FD treatment significantly enhanced spatial memory, preserved pyramidal neuron integrity in CA1 and CA3, and reduced amyloid plaque formation. Biochemically, FD markedly decreased hippocampal Aβ (1-42) and BACE-1 concentrations in a dose-dependent manner. Thus, FD exhibits multi-target neuroprotective effects in an AD-like model, potentially via modulation of amyloidogenic pathways. Further studies are warranted to explore its mechanisms and therapeutic potential in other brain regions implicated in AD.},
}

Animals
*Alzheimer Disease/pathology/drug therapy/metabolism
*Ficus/chemistry
*Neuroprotective Agents/pharmacology/therapeutic use
Male
Rats, Wistar
Disease Models, Animal
*Plant Extracts/pharmacology/therapeutic use
Plaque, Amyloid/pathology/drug therapy
Amyloid beta-Peptides/metabolism
Hippocampus/pathology/drug effects/metabolism
Amyloid Precursor Protein Secretases/metabolism
Maze Learning/drug effects
Rats
*Behavior, Animal/drug effects
Spatial Memory/drug effects
Aspartic Acid Endopeptidases/metabolism

@article {pmid41493656,
year = {2026},
author = {Cicero, CE and Angelini, L and Abbadessa, G and Bruno, M and Fiume, G and Nucera, B and Ornello, R and Arabia, G and Giuliano, L and Guarnieri, B and Lugaresi, A and Perani, D and Sacco, S and Tassorelli, C and Nicoletti, A and Pellecchia, MT and , },
title = {Sex and gender-related differences in neurological diseases: current challenges and recommendations for clinical practice.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {1},
pages = {108},
pmid = {41493656},
issn = {1590-3478},
mesh = {Humans ; *Nervous System Diseases/therapy/epidemiology ; Female ; *Sex Characteristics ; Male ; Pregnancy ; },
abstract = {Neurological diseases include a large variety of conditions ranging from inflammatory, vascular and neurodegenerative disorders to epilepsy and headache. The impact of sex and gender on various aspects of these conditions (epidemiology, risk factors, pathophysiology, clinical features, treatment, and management of pregnancy and breastfeeding) is still not entirely taken into consideration, despite a rapidly increasing body of evidence. This position paper covers six neurological conditions (Alzheimer's Disease, Cerebrovascular disease, Parkinson's disease, Epilepsy, Headache disorders, Multiple Sclerosis) providing an overview of available evidence on sex and gender differences, identifying knowledge gaps and providing recommendations for clinical practice and future studies. We recommend taking into consideration modifiable sex and gender specific risk factors, the role of hormones across women's lifespan and a personalized treatment approach based on gender. We also recommend that future efforts should be devoted to increase the representation of women in clinical studies, to promote sex and gender-based guideline production and to better characterize the safety profile in pregnancy of newer drugs.},
}

Humans
*Nervous System Diseases/therapy/epidemiology
Female
*Sex Characteristics
Male
Pregnancy

@article {pmid41491579,
year = {2026},
author = {Kamali, M and Ansari, M and Nooraee, P and Tajadini, H and Kamali, H and Dehesh, T and Ashrafzadeh, A and Sharififar, F},
title = {Preliminary clinical evaluation of capsules containing standard hydroalcoholic extract of Myrtus communis L. in patients with mild to moderate Alzheimer' disease: a randomized, double-blind parallel-group clinical trial.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-025-04994-9},
pmid = {41491579},
issn = {2662-7671},
abstract = {BACKGROUND: This study evaluated the effectiveness of Myrtus communis L. extract, known for its antioxidant and anticholinesterase properties, to enhance cognitive function and mitigate disease progression in individuals with mild to moderate Alzheimer's disease (AD).

METHODS: Fifty elderly patients with mild to moderate AD residing in a Kerman nursing home were enrolled in a randomized, placebo-controlled trial conducted between November 2019 to February 2020. Participants were randomly assigned to either an intervention group (n = 25), receiving M. communis L. capsules (500 mg each capsule), or a control group (n = 25), receiving placebo capsules. Cognitive function was assessed at baseline and after four weeks using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scales. Statistical analyses, performed using SPSS version 22, considered a significance level of p < 0.05.

RESULTS: All fifty patients completed the four-week trial. Baseline characteristics-including sex, mean age, and education level-were well-matched between the intervention and control groups. After four weeks of treatment, the intervention group demonstrated a statistically significant improvement in cognitive function, as evidenced by significantly higher MMSE scores compared to the placebo group (23.4 ± 0.25 vs. 19.6 ± 0.25; p < 0.0001). Concurrently, the intervention group exhibited a significant reduction in dementia severity, indicated by lower CDR scores compared to the control group (0.8 ± 0.04 vs. 1.5 ± 0.04; p < 0.0001).

CONCLUSIONS: These findings suggest that M. communis L. holds promise as a potential complementary therapy for AD, capable of improving cognitive function and potentially slowing disease progression. However, further research is necessary to corroborate these results, elucidate the underlying mechanisms of action, and optimize treatment parameters before definitive conclusions can be drawn.

TRIAL REGISTRATION: irct.ir, ID: 20170702034861N8. Registered on 26/08/2019.},
}

@article {pmid41491073,
year = {2026},
author = {Wasim, R and Azmi, S and Ahmad, A and Srivastava, A},
title = {NLRP3 inflammasome and Alzheimer's disease: bridging inflammation and neurodegeneration.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41491073},
issn = {1568-5608},
abstract = {The progressive neurodegenerative disease known as Alzheimer's disease (AD) is characterized by widespread neuronal death, memory loss, and cognitive decline. The NLRP3 inflammasome has emerged as a key modulator of neuroinflammation, which is increasingly implicated in the pathophysiology of AD. In response to endogenous and pathogenic danger signals, the innate immune system's multiprotein complex known as the NLRP3 inflammasome is activated. Pyroptosis and neuroinflammatory cascades are eventually triggered by its activation, which causes caspase-1 to be cleaved and pro-inflammatory cytokines like interleukin-1β and interleukin-18 to be released. NLRP3 activation is strongly stimulated by tau aggregation and β-amyloid plaques in AD, which accelerates neuronal damage and prolongs chronic inflammation. The control and activation of inflammasomes are involved in both canonical and non-canonical pathways as well as mitochondrial dysfunction. Significantly, animal models indicate that NLRP3's therapeutic potential is highlighted by the reduction of amyloid burden and amelioration of cognitive decline that results from its inhibition or genetic deletion. Small-molecule inhibitors and natural substances that can alter NLRP3 activity have been discovered recently, providing intriguing approaches to AD treatment. Despite tremendous advancements, issues with medication selectivity and blood-brain barrier penetration still need to be resolved before these discoveries can be used in clinical settings. Comprehending the complex relationship between NLRP3 activation and Alzheimer's pathology may open the door to new, focused treatments meant to slow or stop the progression of the illness.},
}

@article {pmid41490490,
year = {2026},
author = {Wang, W and Huang, R and Lv, L and Ma, X and Li, Z and Zhang, Y and Wu, J and Wu, S and Xu, J and Hu, Y and Turck, CW and Li, H and Hu, X},
title = {Long-term effects of forty-hertz auditory stimulation as a treatment of Alzheimer's disease: Insights from an aged monkey model study.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {2},
pages = {e2529565123},
doi = {10.1073/pnas.2529565123},
pmid = {41490490},
issn = {1091-6490},
mesh = {Animals ; *Alzheimer Disease/therapy/pathology/cerebrospinal fluid ; Macaca mulatta ; tau Proteins/cerebrospinal fluid ; Disease Models, Animal ; Amyloid beta-Peptides/cerebrospinal fluid ; *Acoustic Stimulation/methods ; Male ; Female ; *Aging ; Humans ; Brain/pathology ; },
abstract = {Based mainly on rodents studies, forty-hertz (40-Hz) physical stimulation has been regarded as a potential noninvasive treatment for Alzheimer's disease (AD). Considering the brain differences between rodents and humans, the effects of 40-Hz physical stimulation need to be further validated using nonhuman primates before its clinical application. Here, we took advantage of a rare opportunity to expose nine aged rhesus monkeys (26 to 31 y old) to 40-Hz auditory stimulation. Given the strong correlation between cerebrospinal fluid (CSF) Aβ and Tau concentrations and corresponding AD pathology in brain parenchyma in clinical practice, we investigated the effects of 40-Hz stimulation on AD pathology by monitoring changes in CSF Aβ and Tau concentrations. Our results revealed that 7 consecutive days of 40-Hz auditory stimulation triggered a rapid and significant increase of Aβ levels by more than 200%, but no effect on Tau levels in the CSF. Additionally, we observed that the elevation of CSF Aβ levels persisted for more than 5 wk after cessation, which had not been reported in any previous studies. After this, a pathological examination of the temporal cortices of 4 of the experimental monkeys was carried out and the data demonstrated that all of them had prevalent extracellular Aβ senile plaque pathology, whereas Tau pathology was negative or very weak. These results provide a good explanation for the differences between the CSF Aβ and Tau protein levels. Together, these first-time results from monkeys suggest that 40-Hz auditory stimulation has strong potential of a noninvasive AD treatment method.},
}

Animals
*Alzheimer Disease/therapy/pathology/cerebrospinal fluid
Macaca mulatta
tau Proteins/cerebrospinal fluid
Disease Models, Animal
Amyloid beta-Peptides/cerebrospinal fluid
*Acoustic Stimulation/methods
Male
Female
*Aging
Humans
Brain/pathology

@article {pmid41490210,
year = {2026},
author = {Giuffrè, GM and Battisti, F and Tudor, AM and Lenkowicz, J and Avitabile, A and Rosati, AM and Martellacci, N and Patarnello, S and Torelli, F and Cesario, A and Marra, C},
title = {Redefining management of mild cognitive impairment and Alzheimer's disease through the shift from clinical to clinical-biological diagnosis: Insights from a single-center experience.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411461},
doi = {10.1177/13872877251411461},
pmid = {41490210},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) diagnosis has shifted from a purely clinical framework to a clinical-biological paradigm, driven by biomarker integration. This evolution is motivated by the wider availability of reliable biomarkers and the advent of disease-modifying treatments.ObjectiveTo assess changes over time in clinical characteristics, diagnostic pathways, and healthcare resource utilization in a real-world cohort of individuals with cognitive impairment attending a Memory Clinic.MethodsThis secondary data retrospective observational study analyzed two patient cohorts with newly diagnosed cognitive impairment: one from 2017-2019 and another from 2021-2023. Anonymized medical records and structured hospital data were examined using natural language processing to extract demographic and clinical information, diagnostic pathways, treatment patterns and comorbidities.ResultsThe 2021-2023 cohort was significantly younger, exhibited higher baseline Mini-Mental State Examination scores, and underwent more instrumental assessments than the 2017-2019 cohort. These findings likely reflect a shift in public awareness and attitudes toward cognitive health. AD diagnoses increased in both cohorts over time, while mild cognitive impairment diagnoses declined. The use of diagnostic combinations was more frequent in the recent cohort, in which clinical-biological diagnoses were significantly more prevalent.ConclusionsThis study provides real-world insights into the evolving landscape of cognitive impairment diagnostics and care, underscoring a shift toward earlier, biologically grounded diagnosis, supporting precision medicine in AD care. The expanded use of biomarkers reflects evolving practice standards and prepares the ground for disease-modifying therapies in AD.},
}

@article {pmid41490207,
year = {2026},
author = {Liu, Y and Su, H and Guan, T and Li, X and Dong, C and Hu, Z and Zhang, Y},
title = {Risk prediction of progression from normal cognitive function to Alzheimer's disease in elderly aged 65 and above based on deep learning methods.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410937},
doi = {10.1177/13872877251410937},
pmid = {41490207},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a severe neurological disorder for which a complete cure is not currently available. Therefore, predicting the risk of AD in elderly individuals with normal cognitive function is crucial for early prevention, treatment, and family-provided daily care preparation.ObjectiveThis study aimed to establish a risk prediction model for the progression from normal cognitive function to AD in elderly via deep learning (DL) methods to provide a reference for clinical decision-making and the development of screening tools for the early diagnosis of AD.MethodsDeepSurv, DeepHit, and Cox models were constructed, and the consistency index (C-index), integrated Brier score (IBS), and area under the ROC curve (AUC) were used to evaluate the accuracy, calibration and discriminative power of the three prediction models.ResultsThe overall predictive ability of the model was relatively stable, with concordance indices of 0.82 (DeepSurv), 0.83 (DeepHit), and 0.81 (Cox) and IBSs of 0.08, 0.07, and 0.05, respectively. From the perspective of the C-index indicator, the consistency of the deep learning model was better than that of the Cox model.ConclusionsRisk prediction models for the progression from normal cognitive function to AD can be established using easily obtainable early-stage predictors, which are expected to be used for rapid screening of the risk of developing AD in elderly after clinical validation.},
}

@article {pmid41490027,
year = {2026},
author = {Yang, JW and Jiang, J},
title = {Association between varicella-zoster virus and Alzheimer's disease: A systematic review and meta-analysis of comprehensive evidence from infection, treatment to prevention.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411573},
doi = {10.1177/13872877251411573},
pmid = {41490027},
issn = {1875-8908},
abstract = {BackgroundThe association between varicella-zoster virus (VZV) infection and Alzheimer's disease (AD) risk has shown inconsistent results. Given difficulties in early diagnosis and limited therapeutic options for AD, identifying modifiable risk factors is significant for prevention.ObjectiveTo systematically evaluate the impact of VZV infection on AD risk and explore protective effects of antiviral treatment and vaccination.MethodsWe searched PubMed and Web of Science databases up to April 2025. The Newcastle-Ottawa Scale assessed study quality. Random-effects models were used for meta-analysis using risk ratios (RR) as the primary effect measure, with sensitivity and subgroup analyses conducted.ResultsTwenty-one studies were included. Meta-analysis showed: (1) herpes zoster patients had significantly higher AD risk (RR = 1.12, 95% CI: 1.01-1.24, p = 0.04); (2) patients receiving antiviral treatment had lower AD risk (RR = 0.55, 95% CI: 0.37-0.82, p = 0.003); (3) vaccinated individuals had lower AD risk (RR = 0.72, 95% CI: 0.68-0.78, p < 0.0001). The strongest association occurred in the >70 years age group, demonstrating age as an important effect modifier.ConclusionsThis meta-analysis provides systematic evidence supporting that VZV infection increases AD risk while confirming protective effects of antiviral treatment and vaccination. These findings support including herpes zoster vaccination in preventive healthcare for elderly populations.},
}

@article {pmid41488982,
year = {2025},
author = {Ressa, R and Ettinger, J and Chowdhury, E and Graham, L and Ndirangu, K and Mancebo, JZ and Bodnar, C},
title = {A value assessment of patient-level outcomes and productivity loss for intravenous and subcutaneous lecanemab for patients with early Alzheimer's disease.},
journal = {Journal of medical economics},
volume = {29},
number = {1},
pages = {118-134},
doi = {10.1080/13696998.2025.2609499},
pmid = {41488982},
issn = {1941-837X},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Injections, Subcutaneous ; Markov Chains ; Patient Preference ; Administration, Intravenous ; Cost-Benefit Analysis ; Caregivers ; Efficiency ; Decision Support Techniques ; },
abstract = {AIMS: Intravenous (IV) lecanemab is approved for the treatment of patients with early Alzheimer's disease (AD); a subcutaneous (SC) option may offer additional benefits. We assessed the overall value of SC treatments, and direct/indirect outcomes associated with IV and SC lecanemab.

METHODS AND MATERIALS: For the narrative review, PubMed was searched (February 2025) for studies comparing patient preferences for IV/SC treatment administration published between 2015-2025. Study eligibility was determined using patient, intervention, comparator, outcomes, and study criteria. For the decision-analytic model, a Markov model was developed with four lecanemab treatment scenarios. Scenarios one to three included IV initiation (10 mg/kg biweekly) to month 18, followed by either IV initiation continued (10 mg/kg biweekly), SC maintenance (250 mg weekly) or IV maintenance (10 mg/kg every 4 weeks). Scenario four included SC initiation (500 mg weekly) for an 18-month period, followed by SC maintenance (250 mg weekly). Outcomes were administration time/frequency; patient, caregiver, and healthcare professional time; and caregiver productivity loss.

RESULTS: Forty-three publications reported patient treatment preferences. Most (88.4%) reported that patients preferred SC over IV. Key reasons for this were time savings (n = 13/43 studies; 30.2%), convenience (n = 11/43; 25.6%), treatment frequency (n = 12/43; 27.9%). Two studies (n = 2/43; 4.7%) reported an IV preference over SC; for three studies (n = 3/43; 7.0%), treatment preference was driven by administration frequency. Decision-analytic modeling of lecanemab treatment scenarios revealed that IV initiation to IV maintenance had the lowest number of administrations, whereas SC initiation to SC maintenance had the lowest number of treatment hours and caregiver productivity losses.

LIMITATIONS: Caution must be taken when generalizing these results for all AD patients.

CONCLUSIONS: SC treatments show value as a therapeutic option. IV and SC lecanemab availability may offer benefits to patients, caregivers, and society, and improve shared decision making.},
}

Humans
*Alzheimer Disease/drug therapy
Injections, Subcutaneous
Markov Chains
Patient Preference
Administration, Intravenous
Cost-Benefit Analysis
Caregivers
Efficiency
Decision Support Techniques

@article {pmid41488470,
year = {2026},
author = {Cho, Y and Lee, J and Choi, BY and Yun, JH and Han, S and Baek, SH and Park, J and Cho, Y and Kim, HK and Kim, E and Palomera, LF and Lim, J and Jeon, Y and Im, J and Hong, JM and Kim, TK and Kim, SH and Yim, JH and Jo, DG},
title = {Ramalin Ameliorates Alzheimer's Disease Pathology by Targeting BACE1, HDAC6, and MAPK Pathways.},
journal = {MedComm},
volume = {7},
number = {1},
pages = {e70518},
pmid = {41488470},
issn = {2688-2663},
abstract = {Aberrant deposition of β-amyloid (Aβ) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating β-site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen-activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, Aβ plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed Aβ oligomer-induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease-modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease-modifying candidate with the potential to drive a breakthrough approach targeting AD pathology.},
}

@article {pmid41488323,
year = {2025},
author = {Lotlikar, MS and Zellmer, JC and Bhattacharyya, R},
title = {Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1733659},
pmid = {41488323},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.},
}

@article {pmid41487944,
year = {2026},
author = {Rus Prelog, P and Zupan, M and Gregorič Kramberger, M and Frol, S},
title = {The Concomitant Use of Selective Serotonin Reuptake Inhibitors and Anti-Amyloid Treatment in Alzheimer's Disease: Balancing Benefits and Risks.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {16},
number = {1},
pages = {1-3},
pmid = {41487944},
issn = {1664-5464},
}

@article {pmid41487496,
year = {2025},
author = {Cheng, R and Kim, J},
title = {Intranasal delivery of iron chelators and management of central nervous system disease.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1709259},
pmid = {41487496},
issn = {1663-9812},
abstract = {Brain iron dyshomeostasis plays a critical role in the pathology of multiple central nervous system (CNS) disorders, including neurodegenerative and neuropsychiatric diseases. Iron chelators such as deferoxamine (DFO) and deferiprone (DFP) have demonstrated therapeutic potential in mitigating disease progression in these conditions. However, systemic administration is hindered by poor blood-brain barrier (BBB) permeability, dose-limiting toxicity, and poor patient compliance due to frequent dosing regimens. In recent years, intranasal (IN) drug delivery has emerged as a promising strategy to bypass the BBB, providing a direct nose-to-brain delivery route via olfactory and trigeminal pathways while minimizing systemic exposure. This review provides a comprehensive summary of the current status of iron chelation therapy for CNS disorders with a focus on pharmacokinetics, efficacy, and translational potential of IN administration. While IN DFO has been extensively studied in preclinical models of Alzheimer's disease and stroke, recent developments have expanded the scope to other chelators such as DFP. We compare traditional systemic routes, including oral and intravenous, with intranasal administration, highlighting their respective advantages and limitations for CNS delivery. With ongoing advances in formulation and delivery technologies, IN iron chelators provide a promising alternative for the treatment of CNS disorders characterized by impaired iron homeostasis in the brain.},
}

@article {pmid41487012,
year = {2026},
author = {Verma, R and Bahadur, S},
title = {A Comprehensive Review of Naringin Loaded Nano Drug Delivery System in Treatment of CNS Disorders.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128407188251116030341},
pmid = {41487012},
issn = {1873-4286},
abstract = {Citrus fruits are an abundant source of the polyphenolic phytoconstituent naringenin, which belongs to the class of flavanones. NRG shows a lot of potential as a drug for treating a number of CNS disorders, such as neuroprotective activity, antiamyloidosis, antiparkinson, antialzheimer activity, and more. However, naringenin's hydrophobic nature, which results in limited absorption, limits its therapeutic potential. In this article, we provide an outline of the variety of nanocarriers employed for delivering naringenin as carriers. Some of them include solid lipid nanoparticles, liposomes, micelles, polymeric nanoparticles, nanostructured lipid carriers, nanosuspensions, and nanoemulsions, among others. These formulations of naringenin nanomedicine have been used for the potential treatment of a series of CNS disorders. Based on various research reports, it can be said that with the right nanocarriers, naringenin proves to be a promising therapeutic alternative for the treatment of several CNS ailments, including neurological diseases, Alzheimer's, Parkinson's disease, cerebral ischemia, etc. Therefore, the present manuscript highlights the various aspects of naringenin and its pharmacological activities. Further, naringenin-loaded nanocarriers have been enlisted and discussed in detail.},
}

@article {pmid41486993,
year = {2026},
author = {Cai, M and Yan, S and Sun, Y and Huo, Q and Dai, X},
title = {miRNAs: Promising Biomarkers for Alzheimer's Diagnosis and Treatment.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050427877251118111643},
pmid = {41486993},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, and chronic neuroinflammation, leading to synaptic dysfunction and cognitive decline. Current diagnostic methods rely on clinical symptoms and limited biomarkers, while available treatments only provide symptomatic relief without halting disease progression. MicroRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have emerged as crucial regulators of gene expression through post-transcriptional mechanisms and show distinct dysregulation patterns in AD patients' blood, cerebrospinal fluid (CSF), and brain tissues. Key miRNAs such as miR-132, miR-146a, miR-34a, and miR-125b demonstrate consistent alterations in expression levels, correlating with disease progression and offering potential as non-invasive diagnostic tools. This review comprehensively examines the dual role of miRNAs as diagnostic biomarkers and therapeutic targets for AD. We also provide an analysis of specific miRNA signatures in different biofluids (plasma, serum, CSF) and brain regions that correlate with disease stages, highlighting their potential for early and non-invasive diagnosis. Therapeutically, miRNAs modulate multiple AD-related pathways, including neuroinflammation via NF-κB signaling, Aβ production through BACE1 inhibition, and tau phosphorylation via GSK3β regulation. miRNAs also influence synaptic plasticity, mitochondrial function, and autophagy, presenting multifaceted opportunities for intervention. However, challenges, including miRNA heterogeneity, stability, and targeted delivery, remain critical impediments. Advances in nanocarriers, exosomal miRNAs, and viral vectors show promise in overcoming these obstacles, enabling precise miRNA modulation. In addition, we underscore the need for standardized protocols, further validation in clinical cohorts, and the development of cost-effective detection methods to translate miRNA-based approaches into practical diagnostics and therapies. By integrating miRNA biomarkers with existing diagnostic tools and exploring combinatorial therapeutic strategies, researchers can harness the potential of miRNAs to revolutionize AD intervention, paving the way for early detection and effective treatment of this devastating disease.},
}